Class I MHC glycoproteins are expressed on the surface of all somatic nucleated cells, with the exception of neurons. MHC class I receptors present peptide antigens that are synthesised in the cytoplasm, which includes self-peptides (presented for self-tolerance) as well as foreign peptides (such as viral proteins). These antigens are generated from degraded protein fragments that are transported to the endoplasmic reticulum by TAP proteins (transporter of antigenic peptides), where they can bind MHC I molecules, before being transported to the cell surface via the Golgi apparatus [, ]. MHC class I receptors display antigens for recognition by cytotoxic T cells, which have the ability to destroy viral-infected or malignant (surfeit of self-peptides) cells.MHC class I molecules are comprised of two chains: a MHC alpha chain (heavy chain), and a beta2-microglobulin chain (light chain), where only the alpha chain spans the membrane. The alpha chain has three extracellular domains (alpha 1-3, with alpha1 being at the N terminus), a transmembrane region and a C-terminal cytoplasmic tail. The soluble extracellular beta-2 microglobulin chain associates primarily with the alpha-3 domain and is necessary for MHC stability. The alpha1 and alpha2 domains of the alpha chain are referred to as the recognition region, because the peptide antigen binds in a deep groove between these two domains. This entry represents MHC antigen-recognition-like domains from:MHC class I, alpha-1 and alpha-2 domains []MHC class I homologue gammadelta T-cell ligand []MHC class I related Ulbp3 []MHC class I related Fc (IgG) receptor, alpha-1 and alpha-2 domains []MHC class I related CD1, alpha-1 and alpha-2 domains []MHC class I related zinc-alpha-2-glycoprotein ZAG (fat depleting factor) []Immunomodulatory protein m144, alpha-1 and alpha-2 domains []Haemochromatosis protein Hfe, alpha-1 and alpha-2 domains []Endothelial protein C receptor (phospholipid-binding protein) []NK cell ligand RAE-1 []. RAE-1 proteins (alpha, beta, delta, and gamma) are distant major histocompatibility complex (MHC) class I homologues, comprising isolated alpha-1 alpha-2 domains, and lack alpha3 domains [].
Secretion of virulence factors in Gram-negative bacteria involves transportation of the protein across two membranes to reach the cell exterior. There have been four secretion systems described in animal enteropathogens, such as Salmonella and Yersinia, with further sequence similarities in plant pathogens like Ralstonia and Erwinia [].The type III secretion system is of great interest, as it is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. The protein subunits of the system are very similar to those of bacterial flagellar biosynthesis. However, while the latter forms a ring structure to allow secretion of flagellin and is an integral part ofthe flagellum itself [], type III subunits in the outer membrane translocate secreted proteins through a channel-like structure.Exotoxins secreted by the type III system do not possess a secretion signal, and are considered unique for this reason []. Yersinia secrete a Rho GTPase-activating protein, YopE [, ], that disrupts the host cell actin cytoskeleton. YopE is regulated by another bacterial gene, SycE [], that enables the exotoxin to remain soluble in the bacterial cytoplasm. A similar protein, exoenzyme S from Pseudomonas aeruginosa, has both ADP-ribosylation and GTPase activity [, ]. This entry also includes ADP-ribosyltransferase toxin AexT from Aeromonas salmonicida that is directly involved in the toxicity for RTG-2 (rainbow trout gonad) fish cells [].This entry also includes Exoenzyme T (ExoT) from Pseudomonas aeruginosa. ExoT contains an N-terminal GTPase-activating protein (GAP) domain and a C-terminal ADP-ribosyltransferase (ADPRT) domain. Its ADPRT domain induces atypical anoikis by transforming an innocuous cellular protein, Crk, into a cytotoxin, which interferes with integrin survival signaling. Its GAP domain activity induces mitochondrial disruption in the target host cell by activating host caspases 3 and 9 that execute cellular death [].
Uridylate kinases (also known as UMP kinases) are key enzymes in the synthesis of nucleoside triphosphates. They catalyse the reversible transfer of the gamma-phosphoryl group from an ATP donor to UMP, yielding UDP, which is the starting point for the synthesis of all other pyrimidine nucleotides. The eukaryotic enzyme has a dual specificity, phosphorylating both UMP and CMP, while the bacterial enzyme is specific to UMP. The bacterial enzyme shows no sequence similarity to the eukaryotic enzyme or other nucleoside monophosphate kinases, but rather appears to be part of the amino acid kinase family. It is dependent on magnesium for activity and is activated by GTP and repressed by UTP [, ]. In many bacterial genomes, the gene tends to be located immediately downstream of elongation factor T and upstream of ribosome recycling factor. A related protein family, believed to be equivalent in function is found in the archaea and in spirochetes.Structurally, the bacterial and archaeal proteins are homohexamers centred around a hollow nucleus and organised as a trimer of dimers [, ]. Each monomer within the protein forms the amino acid kinase fold and can be divided into an N-terminal region which binds UMP and mediates intersubunit interactions within the dimer, and a C-terminal region which binds ATP and contains a mobile loop covering the active site. Inhibition of enzyme activity by UTP appears to be due to competition for the binding site for UMP, not allosteric inhibition as was previously suspected.Uridylate kinase PUMPKIN, chloroplastic from Arabidopsis thaliana is essential for retaining photosynthetic activity in chloroplasts as it is required for specific post-transcriptional processes of many plastid transcripts [, ]. This entry represents uridine monophosphate kinase predominantly found in bacteria and plant chloroplasts.
Members of this group are bacterial microcompartment shell proteins: PduT of Salmonella enterica and its orthologs in the propriondiol and ethanolamine operons of bacteria [, , , ]. Some non-autotrophic organisms form polyhedral organelles, enterosomes [], that resemble the carboxysomes found in autotrophs, particularly the cyanobacteria. Carboxysomes are well-studied polyhedral organelles found in cyanobacteria and some chemoautotrophs [, ]. They are composed of a proteinaceous shell that houses most of the cell s ribulose bisphosphate carboxylase/oxygenase (RuBisCO). They are required for autotrophic growth at low CO2concentrations and are thought to function as part of a CO2-concentrating mechanism [, ].Polyhedral organelles, enterosomes, from non-autotrophic organisms are involved in coenzyme B12-dependent 1,2-propanediol utilization (e.g., in S. enterica, []) and ethanolamine utilization (e.g., in Salmonella typhimurium []). Genes needed for enterosome formation are located in the 1,2-propanediol utilization pdu[, ]or ethanolamine utilization eut[, ]operons, respectively. Although enterosomes of non-autotrophic organisms are apparently related to carboxysomes structurally, a functional relationship is uncertain. A role in CO2concentration, similar to that of the carboxysome, is unlikely since there is no known association between CO2and coenzyme B12-dependent 1,2-propanediol or ethanolamine utilization [].In S. enterica the propriondiol degrading enterosome consists of at least 15 proteins, of which, at least, seven are shell proteins: pduA [], pduB, B', J, K, T and U. In addition the organelle contains four enzymes: B12-dependent diol dehydratase (pduCDE) and its reactivating factor (pduGH), CoA-dependent proprionaldehyde dehydrogenase (pduP, []) and adenosyl transferase (pduO) []. It has been suggested that enterosomes sequester toxic aldehydes formed during both 1,2-propanediol and ethanolamine degradation and channel them to subsequent pathway enzymes. It has also been suggested that polyhedra might be used to protect diol dehydratase and ethanolamine ammonia-lyase from oxygen, to which both are sensitive [, ]. Mutational studies of PduA indicate that the organelles of S. enterica are not involved in concentrating 1,2-propanediol or CN-B12, but are consistent with a role in moderating aldehyde toxicity [, ].
This entry represent the C3HC5-type RING-HC finger found in MGRN1/RNF157 and related proteins. It is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.MGRN1 is a cytosolic E3 ubiquitin-protein ligase that inhibits signalling through the G protein-coupled melanocortin receptors-1 (MC1R), -2 (MC2R) and -4 (MC4R) via ubiquitylation-dependent and -independent processes []. It suppresses chaperone-associated misfolded protein aggregation and toxicity []. MGRN1 interacts with cytosolic prion proteins (PrPs) that are linked with neurodegeneration[]. It also interacts with expanded polyglutamine proteins, and suppresses misfolded polyglutamine aggregation and cytotoxicity. Moreover, MGRN1 inhibits melanocortin receptor signaling by competition with Galphas, suggesting a novel pathway for melanocortin signaling from the cell surface to the nucleus []. Furthermore, MGRN1 interacts with and ubiquitylates TSG101, a key component of the endosomal sorting complex required for transport (ESCRT)-I, and regulates endosomal trafficking. A null mutation in the gene encoding MGRN1 causes spongiform neurodegeneration, suggesting a link between dysregulation of endosomal trafficking and spongiform neurodegeneration [, ].RNF157 is a cytoplasmic E3 ubiquitin ligase predominantly expressed in brain. In cultured neurons, it promotes neuronal survival in an E3 ligase-dependent manner. In contrast, it supports growth and maintenance of dendrites independent of its E3 ligase activity. RNF157 interacts with and ubiquitinates the adaptor protein APBB1 (amyloid beta precursor protein-binding, family B, member 1 or Fe65), which regulates neuronal survival, but not dendritic growth downstream of RNF157. The nuclear localization of APBB1 together with its interaction partner RNA-binding protein SART3 (squamous cell carcinoma antigen recognized by T cells 3 or Tip110) is crucial to trigger apoptosis []. Both MGRN1 and RNF157 contain a modified C3HC5-type RING-HC finger, and a functionally uncharacterized region, known as domain associated with RING2 (DAR2), N-terminal to the RING finger.In Arabidopsis, LOG2 is a predicted E3 ubiquitin ligase that interact with GDU1 and is involved in the regulation of amino acid export from plant cells [].
The variable portions of immunoglobulin and T cell receptor genes are assembled in developing lymphocytes from variable (V), joining (J), and in some cases diversity (D) gene segments, which are widely separated in the genome. These segments are brought together in a highly regulated manner by a somatic site-specific recombination reaction known as V(D)J recombination. Each gene segment is flanked by a signal sequence consisting of a conserved heptamer (consensus sequence 5'-CACAGTG-3') and nonamer (consensus sequence 5'-ACAAAAACC-3') separated by a relatively nonconserved 12 or 23 base pair (bp) spacer (12 signal or 23 signal, respectively). A segment flanked by a 12 signal can only be joined efficiently to one flanked by a 23 signal, a restriction referred to as the 12/23 rule [].The V(D)J recombinase subunits Rag-1 and Rag-2 (recombination activating gene) mediate assembly of antigen receptor gene segments. The critical step for signal recognition is binding of Rag-1 to the nonamer []. The Rag-1 nonamer binding domain (NBD) forms a tightly interwoven dimer that binds and synapses two nonamer elements, with each NBD making contact with both DNA molecules. Each NBD monomer is composed of three helices: H1, H2 and H3. Helix 1 contains a kink that separates it into two smaller helices: H1a and H1b. Helices H2 and H3 from each subunit form a four-helix bundle through extensive hydrophobic interactions and constitute the bulk of the dimer interface, whereas the H1 helices from the two subunits wrap around one side of the four-helix bundle with the N-terminal GGRPR motifs protruding from opposite sides of the dimer. The GGRPR motif is an example of an AT-hook, a structural element found in various DNA binding proteins [].
AIRE (AutoImmune REgulator) is a transcription factor that plays an essential role to promote self-tolerance in the thymus by regulating the expression of a wide array of self-antigens that have the commonality of being tissue-restricted in their expression pattern in the periphery, called tissue restricted antigens (TRA) [, ]. Mutations cause a rare autosomal recessively inherited disease termed APECED. APECED, also called Autoimmune Polyglandular Syndrome type I (APS 1), is the only described autoimmune disease with established monogenic background, being localised outside the major histocompatibility complex region. It is characterised by the presence of two of the three major clinical entities, chronic mucocutaneus candidiasis, hypoparathyroidism and Addison's disease. Other immunologically mediated phenotypes, including insulin-dependent diabetes mellitus (IDDM), gonadal failure, chronic gastritis, vitiligo, autoimmune thyroid disease, enamel hypoplasia, and alopecia may also be present. Immunologically, APECED patients have deficient T cell responses towards Candida antigens, and clinical symptoms both within and outside the endocrine system, mainly as a result of autoimmunity against organ-specific autoantigens [, ].AIRE has a HSR/CARD domain involved in promoting AIRE to multimerise to itself, a SAND domain that appears to be involved in promoting a protein-protein interaction with a transcriptional repressive complex and two zinc fingers of the plant homodomain (PHD) type PHD1 and PHD2, of which PHD1 functions as a histone code reader [, , , ].AIRE has a dual subcellular location. It is not only expressed in multiple immunologically relevant tissues, such as the thymus, spleen, lymph nodes and bone marrow, but it has also been detected in various other tissues, such as kidney, testis, adrenal glands, liver and ovary, suggesting that APECED proteins might also have a function outside the immune system. However, AIRE is not expressed in the target organs of autoimmune destruction. At the subcellular level, AIRE can be found in the cell nucleus in a speckled pattern in domains resembling promyeolocytic leukaemia nuclear bodies, also known as ND10, nuclear dots or potential oncogenic domains associated with the AIRE homologous nuclear proteins Sp100, Sp140, and Lysp100.
Interferon (IFN)-gamma is a dimeric glycoprotein produced by activated T cells and natural killer cells. Although originally isolated based on itsantiviral activity, IFN-gamma also displays powerful anti-proliferative and immunomodulatory activities, which are essential for developing appropriate cellular defences against a variety of infectious agents. The first step in eliciting these responses is the specific high affinity interaction of IFN-gamma with its cell-surface receptor (IFN-gammaRalpha); the complex then interacts with at least one of a family of additional species-specific accessory factors (AF-1 or IFN-gammabeta), which convey different cellular responses. One such response is the association and phosphorylation of two protein tyrosine kinases (Jak-1 and Jak-2), which in turn stimulate nuclear transcription activators [].This entry includes:The human IFN-gamma receptor 1 (IFN-gammaR1), a member of the hematopoietic cytokine receptor superfamily. It is expressed in a membrane-bound form in many cell types, and is over-expressed in tumour cells. It comprises an extracellular portion of 229 residues, a single transmembrane region, and a cytoplasmic domain of 221 residues. As with other members of its superfamily, the cytokine-binding sites are formed by a small set of closely-spaced surface loops that extend from a β-sheet core, much like antigen-binding sites on antibodies. The extracellular IFN-gammaR monomer comprises two domains (D1 and D2 domains), each resembling an Ig-like fold with fibronectin type III topology [, , ]. The signalling complex comprises two IFN-gammaR1 chains and two IFN-gammaR2 chains, which dimerises in an IFN-gamma-driven fashion [].The vaccinia virus interferon (IFN)-gamma receptor (IFN-gammaR) is a 43kDa soluble glycoprotein that is secreted from infected cells early during infection. IFN-gammaR from vaccinia virus, cowpoxvirus and camelpox virus exist naturally as homodimers, whereas the cellular IFN-gammaR dimerizes only upon binding the homodimeric IFN-gamma. The existence of the virus protein as a dimer in the absence of ligand may provide an advantage to the virus in efficient binding and inhibition of IFN-gamma in solution [].This is the D2 domain, which is involved in forming receptor-receptor contacts [].
This entry represents a group of confirmed and predicted E3 ubiquitin ligases, including MGRN1/RNF157 from humans and LOG2/LUL1-4 from Arabidopsis.MGRN1 is a cytosolic E3 ubiquitin-protein ligase that inhibits signalling through the G protein-coupled melanocortin receptors-1 (MC1R), -2 (MC2R) and -4 (MC4R) via ubiquitylation-dependent and -independent processes []. It suppresses chaperone-associated misfolded protein aggregation and toxicity []. MGRN1 interacts with cytosolic prion proteins (PrPs) that are linked with neurodegeneration[]. It also interacts with expanded polyglutamine proteins, and suppresses misfolded polyglutamine aggregation and cytotoxicity. Moreover, MGRN1 inhibits melanocortin receptor signaling by competition with Galphas, suggesting a novel pathway for melanocortin signaling from the cell surface to the nucleus []. Furthermore, MGRN1 interacts with and ubiquitylates TSG101, a key component of the endosomal sorting complex required for transport (ESCRT)-I, and regulates endosomal trafficking. A null mutation in the gene encoding MGRN1 causes spongiform neurodegeneration, suggesting a link between dysregulation of endosomal trafficking and spongiform neurodegeneration [, ].RNF157 is a cytoplasmic E3 ubiquitin ligase predominantly expressed in brain. In cultured neurons, it promotes neuronal survival in an E3 ligase-dependent manner. In contrast, it supports growth and maintenance of dendrites independent of its E3 ligase activity. RNF157 interacts with and ubiquitinates the adaptor protein APBB1 (amyloid beta precursor protein-binding, family B, member 1 or Fe65), which regulates neuronal survival, but not dendritic growth downstream of RNF157. The nuclear localization of APBB1 together with its interaction partner RNA-binding protein SART3 (squamous cell carcinoma antigen recognized by T cells 3 or Tip110) is crucial to trigger apoptosis []. Both MGRN1 and RNF157 contain a modified C3HC5-type RING-HC finger, and a functionally uncharacterized region, known as domain associated with RING2 (DAR2), N-terminal to the RING finger.In Arabidopsis, LOG2 is a predicted E3 ubiquitin ligase that interact with GDU1 and is involved in the regulation of amino acid export from plant cells [].
5'-nucleotidases []are enzymes that catalyze the hydrolysis ofphosphate esterified at carbon 5' of the ribose and deoxyribose portions ofnucleotide molecules. 5'-nucleotidase is a ubiquitous enzyme found in a widevariety of species and which occurs in different cellular locations. The extracellular 5'-nucleotidase from mammals and Discopyge ommata (Electric ray) isozyme is a homodimeric disulphide-bonded glycoprotein attached to the membrane by a GPI-anchor, and requires zinc for its activity. Vibrio parahaemolyticus 5'-nucleotidase (gene nutA) is bound to the membrane by a lipid chain, and requires chloride and magnesium ions for its activity. It is involved in degrading extracellular 5'-nucleotides for nutritional needs.Periplasmic bacterial 5'-nucleotidase (gene ushA), also knownas UDP-sugar hydrolase , can degrade UDP-glucose and other nucleotide diphosphate sugars. It produces sugar-1-phosphate which can then be used by the cell. UshA seems to require cobalt for its activity.5'-Nucleotidases are evolutionary related to the periplasmic bacterial 2',3'-cyclic-nucleotide 2'-phosphodiesterase (gene cpdB), which catalyzes two consecutive reactions: it first converts 2',3'-cyclic-nucleotide to 3'-nucleotide and then acts as a 3'-nucleotidase; and mosquito apyrase (ATP-diphosphohydrolase) [], which catalyzes the hydrolysis of ATP into AMP and facilitates hematophagy by preventing ADP-dependent platelet aggregation in the host.CD73 (also called ecto-5'-nucleotidase) possesses the enzymatic activity of a 5'-nucleotidase and catalyses the dephosphorylation of purine and pyrimidine ribo- and deoxyribonucleoside monophosphates to their corresponding nucleosides. Triggering of lymphocyte CD73 with mAb causes phosphorylation and dephosphorylation of certain, yet unknown protein substrates []. A possible function for CD73 is to regulate the availability of adenosine for interaction with cell surface adenosine receptor by converting AMP to adenosine. In common with other GPI anchored surface proteins CD73 can mediate costimulatory signals in T cell activation [].This entry is the C-terminal domain of 5'-nucleotidases.
Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).CC chemokine receptors are a subfamily of the chemokine receptors that specifically bind and respond to cytokines of the CC chemokine family. There are currently ten members of the CC chemokine receptor subfamily, named CCR1 to 10. The receptors receptors are found in monocytes, lymphocytes, basophils and eosinophils.This entry represents CC chemokine receptor 6 (CCR6). It is expressed on unactivated memory T-cells [, ]and some dendritic cells [, ]. CCR6 is also expressed on Th17 cells [], but is down-regulated in activated T-cells []. The receptor is noted as playing a role in Crohn's disease []. CCR6 major ligand is CCL20, also known as Liver and Activation-Regulated Chemokine but it can also bind non-chemokine ligands such as beta-defensines [, ]. Binding to beta-defensine 1 (DEFB1) is essential for the function of DEFB1 in regulating sperm motility and bactericidal activity []and it mediates the chemotactic effects of defensins DEFB4 and DEFB4A/B [].
Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).CC chemokine receptors are a subfamily of the chemokine receptors that specifically bind and respond to cytokines of the CC chemokine family. There are currently ten members of the CC chemokine receptor subfamily, named CCR1 to 10. The receptors receptors are found in monocytes, lymphocytes, basophils and eosinophils.This entry represents CC chemokine receptor 8 (CCR8), which it is expressed predominantly in lymphoid tissues [, ]and has also been found in glomerular podocytes []and human umbilical vein endothelial cells (HUVECs) []. CCR8 is associated with Th2 lymphocytes, which are critical for allergy, and has a role in lymphocyte activation, migration, proliferation and differentiation and in allergic diseases [, , ]. CCR8 binds to CCL1 (also known as I-309) [, ]and to CCL16 (also known as liver expressed chemokine) []. It also exhibits a high affinity for three chemokines of viral origin: vMIP-I, vMIP-II and vMCC-I.
This group represents QueF-like proteins, closely related to (QueF/YkvM) but containing an additional N-terminal domain. They are predicted to function as NADPH-dependent nitrile oxidoreductase based on sequence similarity to , and to catalyse the NADPH-dependent reduction of 7-cyano-7-deazaguanineto7-aminomethyl-7-deazaguanine, a late step in the biosynthesis of queuosine, a 7-deazaguanine modified nucleoside found in tRNA(GUN) of bacteria and eukaryotes.Queuosine (Q) is an example of a highly modified nucleoside located in the anticodon wobble position 34 of tRNAs specific for Tyr, His, Asp, and Asn. With few exceptions (such as yeast and mycoplasma), it is widely distributed in most prokaryotic and eukaryotic phyla []. Q is based on a very unusual 7-deazaguanosine core, which is further modified by addition of a cyclopentendiol ring [].This group of proteins belongs to the T fold structural superfamily and is related to GTP cyclohydrolase FolE. QueF-like proteins form two groups, type I proteins exemplified by Bacillus subtilis YkvM () and type II proteins exemplified by Escherichia coli YqcD (). The type I proteins are comparable in size with bacterial and mammalian FolE, whereas the type II proteins are larger and are predicted to be comprised of two domains, similar to plant FolE [].In members of this entry, the N-terminal domain has often been annotated as a membrane-spanning domain, but transmembrane prediction programs run on YqcD do not detect any transmembrane segments []. Instead, the QueF motif can be easily detected in this domain, whereas the flanking and invariant cysteine and glutamate residues (Cys-190 and Glu-230 in E. coli YqcD) are only present in the C-terminal domain. The splitting of active-site residues between the two domains of YqcD is very similar to that seen in two-domain FolE, in which neither domain contains the full set of active site residues nor is active when expressed separately. Further, the pattern of active-site splitting is the same in both proteins, with a similarly located conserved central sequence motif split from two flanking sequences, which are 40 residues apart. The splitting of the YqcD active site suggests that a gene duplication occurred, with each domain retaining some of the residues of the putative active site []. As in two-domain FolE, such a duplication event and redistribution of active-site residues could allow the YqcD proteins to evolve a simpler quaternary structure than the QueF proteins [].
This group of sequences represent the p10 subunit found in caspases. Caspases (Cysteine-dependent ASPartyl-specific proteASE) are cysteine peptidases that belong to the MEROPS peptidase family C14 (caspase family, clan CD) based on the architecture of their catalytic dyad or triad []. Caspases are tightly regulated proteins that require zymogen activation to become active, and once active can be regulated by caspase inhibitors. Activated caspases act as cysteine proteases, using the sulphydryl group of a cysteine side chain for catalysing peptide bond cleavage at aspartyl residues in their substrates. The catalytic cysteine and histidine residues are on the p20 subunit after cleavage of the p45 precursor.Caspases are mainly involved in mediating cell death (apoptosis) [, , ]. They have two main roles within the apoptosis cascade: as initiators that trigger the cell death process, and as effectors of the process itself. Caspase-mediated apoptosis follows two main pathways, one extrinsic and the other intrinsic or mitochondrial-mediated. The extrinsic pathway involves the stimulation of various TNF (tumour necrosis factor) cell surface receptors on cells targeted to die by various TNF cytokines that are produced by cells such as cytotoxic T cells. The activated receptor transmits the signal to the cytoplasm by recruiting FADD, which forms a death-inducing signalling complex (DISC) with caspase-8. The subsequent activation of caspase-8 initiates the apoptosis cascade involving caspases 3, 4, 6, 7, 9 and 10. The intrinsic pathway arises from signals that originate within the cell as a consequence of cellular stress or DNA damage. The stimulation or inhibition of different Bcl-2 family receptors results in the leakage of cytochrome c from the mitochondria, and the formation of an apoptosome composed of cytochrome c, Apaf1 and caspase-9. The subsequent activation of caspase-9 initiates the apoptosis cascade involving caspases 3 and 7, among others. At the end of the cascade, caspases act on a variety of signal transduction proteins, cytoskeletal and nuclear proteins, chromatin-modifying proteins, DNA repair proteins and endonucleases that destroy the cell by disintegrating its contents, including its DNA. The different caspases have different domain architectures depending upon where they fit into the apoptosis cascades, however they all carry the catalytic p10 and p20 subunits.Caspases can have roles other than in apoptosis, such as caspase-1 (interleukin-1 beta convertase) (), which is involved in the inflammatory process. The activation of apoptosis can sometimes lead to caspase-1 activation, providing a link between apoptosis and inflammation, such as during the targeting of infected cells. Caspases may also be involved in cell differentiation [].
Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).CC chemokine receptors are a subfamily of the chemokine receptors that specifically bind and respond to cytokines of the CC chemokine family. There are currently ten members of the CC chemokine receptor subfamily, named CCR1 to 10. The receptors receptors are found in monocytes, lymphocytes, basophils and eosinophils.This entry represents CC chemokine receptor 2 (CCR2), it is a receptor for the monocyte chemoattractant protein-1 (CCL2), a chemokine which specifically mediates monocyte chemotaxisis involved in monocyte infiltration in inflammatory diseases such as rheumatoid arthritis []as well as in the inflammatory response against tumors []. It has also been shown that CCR2 deficient mice develop an accelerated Alzheimer's-like pathology in comparison to wild type mice [, , ]. CCR2 has also been shown to function in blood vessel remodeling []. Following interaction with specific CC chemokine ligands, CCR2 triggers a flux in intracellular calcium ions [, ]and inhibition of adenylyl cyclase []. This causes cell responses, including the recruitment of mononuclear phagocytes into the CNS, leading to chemotaxis [].
Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).CC chemokine receptors are a subfamily of the chemokine receptors that specifically bind and respond to cytokines of the CC chemokine family. There are currently ten members of the CC chemokine receptor subfamily, named CCR1 to 10. The receptors receptors are found in monocytes, lymphocytes, basophils and eosinophils.This entry represents CC chemokine receptor 1 (CCR1). In humans, it is found on peripheral blood lymphocytes and monocytes [, , ]. Immunologically mediated inflammatory disease indications have been suggested for CCR1 [, ], including cardiac allograft rejection []and glomerulonephritis []. Following interaction with specific CC chemokine ligands, CCR1 triggers a flux in intracellular calcium ions [, , ]. This causes cell responses, including the recruitment of mononuclear phagocytes into the CNS, leading to chemotaxis [, , , ].
Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).CC chemokine receptors are a subfamily of the chemokine receptors that specifically bind and respond to cytokines of the CC chemokine family. There are currently ten members of the CC chemokine receptor subfamily, named CCR1 to 10. The receptors receptors are found in monocytes, lymphocytes, basophils and eosinophils.This entry represents CC chemokine receptor 1 (CCR1). In humans, it is found on peripheral blood lymphocytes and monocytes [, , ]. Immunologically mediated inflammatory disease indications have been suggested for CCR1 [, ], including cardiac allograft rejection []and glomerulonephritis []. Following interaction with specific CC chemokine ligands, CCR1 triggers a flux in intracellular calcium ions [, , ]. This causes cell responses, including the recruitment of mononuclear phagocytes into the CNS, leading to chemotaxis [, , , ].This entry includes C-C chemokine receptor type 1 from eukaryotes.
Cannabinoid receptors are a class of cell membrane receptors that belong to the rhodopsin-like G-protein coupled receptor (GPCR) family [, , ]. Typical of G protein-coupled receptors, cannabinoid receptors contain seven transmembrane spanning domains []. Cannabinoid receptors are activated by three major groups of ligands: endocannabinoids, such as N-arachidonoylethanolamine and 2-arachidonoyl glycerol (produced by the mammalian body), plant cannabinoids, such as tetrahydrocannabinol [, ](produced by the plant Cannabis sativa ) and synthetic cannabinoids, such as HU-210 []. Currently, two known cannabinoid receptor subtypes have been identified, CB1 receptor and CB2 receptor [, ], and are phylogenetically restricted to the chordate branch of the animal kingdom []. The International Union of Basic and Clinical Pharmacology (IUPHAR) has identified five pharmacological targets that could be used to find new cannabinoid receptors or channels [], which has resulted in a number of cannabinoid receptors being considered. TRP vanilloid 1 (), which is thought to function as an ionotropic cannabinoid receptor [], and some deorphanised GPCRs []: GPR18, GPR55, GPR119. However, according to the criteria, no channel, non-CB1/CB2 established receptor or deorphanised receptor can currently be classified fully as anovel cannabinoid receptor [].This entry represents cannabinoid receptor 2 (CB2), which is found primarily in immune tissue [], specifically T cells of the immune system, on macrophages and B cells, and in hematopoietic cells [, ]. The CB2 receptor is closely related to CB1 receptor exhibiting 68% homology []. The CB2 receptor has been shown to bind cannabinoid and aminoalkylindole compounds and to signal a response through the inhibition of adenylate cyclase [, , , , ]. The principal endogenous ligand for the CB2 receptor is 2-arachidonoylglycerol (2-AG) [, , ]. The primary effect of the CB2 receptor is mainly on the immunological activity of leukocytes [], and it has specifically been implicated in a variety of modulatory functions, including immune suppression, induction of apoptosis, and induction of cell migration [, ]. CB2 receptors may have possible therapeutic roles in the treatment of neurodegenerative disorders such as Alzheimer's disease [, ].
Members of this group are involved in the biosynthesis of queuosine, a 7-deazaguanine-modified nucleoside found in tRNA(GUN) of Bacteria and Eukarya. QueF (YkvM) from Bacillus subtilis has been shown to catalyse the NADPH-dependent reduction of 7-cyano-7-deazaguanine to 7-aminomethyl-7-deazaguanine, a late step in the biosynthesis of queuosine [].Queuosine is located in the anticodon wobble position 34 of tRNAs specific for Tyr, His, Asp, and Asn. With few exceptions (such as yeast and mycoplasma), it is widely distributed in most prokaryotes and eukaryotes []. Queuosine is based on a very unusual 7-deazaguanosine core, which is further modified by addition of a cyclopentendiol ring [].This group of proteins belongs to the T fold structural superfamily and is related to GTP cyclohydrolase (GTP-CH-I) FolE. Two major features differentiate the QueF and FolE groups. First, the strictly conserved QueF motif E-78(S/L)K(S/A)hK(L/Y)(Y/F/W)-85 (residue numbers are those of B. subtilis YkvM, h is hydrophobic amino acid) is characteristic of the QueF family, but is not found in the FolE family. Second, four catalytically important residues in FolE [], His-112, 113, and 179 and Cys-181 (Escherichia coli FolE numbering), are absent in the QueF group.QueF-like proteins form two groups, type I proteins exemplified by Bacillus subtilis YkvM () and type II proteins exemplified by Escherichia coli YqcD (). The type I proteins are comparable in size with bacterial and mammalian FolE, whereas the type II proteins are larger and are predicted to be comprised of two domains, similar to plant FolE [].The discovery of oxidoreductase activity within the FolE scaffold is an intriguing example of structural and functional evolution, particularly in light of the need to bind a second organic substrate, the cofactor NADPH. The specificity of the QueF motif to the QueF family suggests that these residues might be involved in NADPH binding []. Additionally, the binding of a modified base to QueF, instead of the nucleotide to FolE, in principle leaves vacant in QueF the binding site occupied by the ribosyl portion of GTP. This putative "empty"ribosyl pocket might also contribute to NADPH binding [].
Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).The CXC chemokine receptors are a subfamily of chemokine receptors that specifically bind and respond to cytokines of the CXC chemokine family. There are currently seven known CXC chemokine receptors in mammals, CXCR1 through to CXCR7.CXCR1 and CXCR2, also known as interleukin 8 receptor alpha and beta, respectively [], are closely-related receptors. They act as specific receptors for the CXCL8 and CXCL6 chemokines, which have a glutamate-leucine-arginine (ELR) motif in their N-terminal domains []. CXCR2 also binds additional ELR motif-containing CXC chemokines (such as CXCL1, CXCL2, CXCL3, CXCL5 and CXCL7) with high affinity [].CXCR1 and CXCR2 are expressed on all granulocytes, monocytes, and mast cells and on some CD8+ T-cells and CD56+ natural killer (NK) cells []. Equal amounts of CXCR1 and CXCR2 are present on neutrophils [, , , , ], but it appears that monocytes and positive lymphocytes express more CXCR2 than CXCR1 [].This entry represents both CXCR1 and CXCR2.
Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).The CXC chemokine receptors are a subfamily of chemokine receptors that specifically bind and respond to cytokines of the CXC chemokine family. There are currently seven known CXC chemokine receptors in mammals, CXCR1 through to CXCR7.CXCR1 and CXCR2, also known as interleukin 8 receptor alpha and beta, respectively [], are closely-relatedreceptors. They act as specific receptors for the CXCL8 and CXCL6 chemokines, which have a glutamate-leucine-arginine (ELR) motif in their N-terminal domains []. CXCR2 also binds additional ELR motif-containing CXC chemokines (such as CXCL1, CXCL2, CXCL3, CXCL5 and CXCL7) with high affinity [].CXCR1 and CXCR2 are expressed on all granulocytes, monocytes, and mast cells and on some CD8+ T-cells and CD56+ natural killer (NK) cells []. Equal amounts of CXCR1 and CXCR2 are present on neutrophils [, , , , ], but it appears that monocytes and positive lymphocytes express more CXCR2 than CXCR1 [].This entry represents CXCR2. The angiogenic effects of CXCL8 in intestinal microvascular endothelial cells are mediated by this receptor []. It has been suggested that the receptor may be a potential theraputic target in acute lung injury [].
Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).The CXC chemokine receptors are a subfamily of chemokine receptors that specifically bind and respond to cytokines of the CXC chemokine family. There are currently seven known CXC chemokine receptors in mammals, CXCR1 through to CXCR7.CXCR1 and CXCR2, also known as interleukin 8 receptor alpha and beta, respectively [], are closely-related receptors. They act as specific receptors for the CXCL8 and CXCL6 chemokines, which have a glutamate-leucine-arginine (ELR) motif in their N-terminal domains []. CXCR2 also binds additional ELR motif-containing CXC chemokines (such as CXCL1, CXCL2, CXCL3, CXCL5 and CXCL7) with high affinity [].CXCR1 and CXCR2 are expressed on all granulocytes, monocytes, and mast cells and on some CD8+ T-cells and CD56+ natural killer (NK) cells []. Equal amounts of CXCR1 and CXCR2 are present on neutrophils [, , , , ], but it appears that monocytes and positive lymphocytes express more CXCR2 than CXCR1 [].This entry represents CXCR1
Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).CC chemokine receptors are a subfamily of the chemokine receptors that specifically bind and respond to cytokines of the CC chemokine family. There are currently ten members of the CC chemokine receptor subfamily, named CCR1 to 10. The receptors receptors are found in monocytes, lymphocytes, basophils and eosinophils.This entry represents CC chemokine receptor 7 (CCR7). It is expressed in various lymphoid tissues and plays an important role in the regulation of the homing and traffic of lymphocytes into and within secondary lymphoid tissues [, , , ]. It has also been shown to induce antiapoptotic signaling in mature dendritic cells []. CCR7 is seen as an important organiser of the primary immune response []. CCR7 is also expressed by various cancer cells, such as non-small lung cancer, gastric cancer and oesophageal cancer [, , ]and the expression of CCR7 by cancer cells has been linked with metastasis to lymph nodes []. CCR7 binds CCL19 and CCL21 [].
These proteins contain a domain found in serine peptidases belonging to the MEROPS peptidase families S8 (subfamilies S8A (subtilisin) and S8B (kexin) and S53 (sedolisin), both of which are members of clan SB [].The subtilisin family is one of the largest serine peptidase families characterised to date. Over 200 subtilises are presently known, more than 170 of which with their complete amino acid sequence []. It is widespread, being found in eubacteria, archaebacteria, eukaryotes and viruses []. The vast majority of the family are endopeptidases, although there is an exopeptidase, tripeptidyl peptidase [, ]. Structures have been determined for several members of the subtilisin family: they exploit the same catalytic triad as the chymotrypsins, although the residues occur in a different order (HDS in chymotrypsin and DHS in subtilisin), but the structures show no other similarity [, ]. Some subtilisins are mosaic proteins, while others contain N- and C-terminal extensions that show no sequence similarity to any other known protein [].The proprotein-processing endopeptidases kexin, furin and related enzymesform a distinct subfamily known as the kexin subfamily (S8B). These preferentially cleave C-terminally to paired basic amino acids. Members of this subfamily can be identified by subtly different motifs around the active site [, ]. Members of the kexin subfamily, along with endopeptidases R, T and K from the yeast Tritirachium and cuticle-degrading peptidase from Metarhizium, require thiol activation. This can be attributed to the presence of a cysteine near to the active site histidine []. Only one viral member of the subtilisin family is known, a 56kDa protease from herpes virus 1, which infects the channel catfish []. Sedolisins (serine-carboxyl peptidases) are proteolytic enzymes whose fold resembles that of subtilisin; however, they are considerably larger, with the mature catalytic domains containing approximately 375 amino acids. The defining features of these enzymes are a unique catalytic triad, Ser-Glu-Asp, as well as the presence of an aspartic acid residue in the oxyanion hole. High-resolution crystal structures have now been solved for sedolisin from Pseudomonas sp. 101, as well as for kumamolisin from a thermophilic bacterium, Bacillus sp. MN-32. Mutations in the human gene leads to a fatal neurodegenerative disease [].
Histamine plays an important role in a variety of pathophysiological conditions. In allergic conditions, histamine is released from basophils and mast cells and is responsible for symptoms of allergic conditions of the skin and airways. In the gastric mucosa, gastric induced histamine release stimulates parietal cells to secrete gastric acid. In the central nervous system (CNS), histamine is synthesized in specific neurons that are localized in the posterior hypothalamus. These neurons are involved in a variety of important physiological functions, including the regulation of the sleep-wake cycle, cardiovascular control, regulation of the hypothalamic pituitary adrenal-axis, learning and memory [, , , , ].Histamine exerts its biological effects by binding to and activating four distinct separate rhodopsin-like G protein-coupled receptors-histamine H1 receptor, histamine H2 receptor, histamine H3 receptor, and histamine H4 receptor. Each of the histamine receptors produce a functional response, but their mechanism differs. The H1 receptor couples to Gq/11 stimulating phospholipase C, whereas the H2 receptor interacts with Gs to activate adenylyl cyclase []. The H3 and H4 receptors couple to Gi proteins to inhibit adenylyl cyclase, and to stimulate MAPK in the case of the H3 receptor [, ].This entry represents the histamine H2 receptor (also known as HH2R). It is located in parietal cells found in the stomach and in the heart and has a limited distribution in vascular smooth muscle and cells of the immune system. H2 receptors primarily stimulate gastric acid secretion and vasodilation, H2 antagonists are therefore used in the clinical treatment of peptic ulceration and asthma [, , ]. Activation of the H2 receptor results in physiological responses, including stimulation of suppressor T cells, decrease in neutrophil and basophil chemotaxis and activation, proliferation of lymphocytes and activity of natural killer cells []. H2 receptors are a potent stimulant of cAMP production []and increases intracellular Ca2+ concentrations and releases Ca2+ from the intracellular stores []. A combination of both H1 and H2 antihistamines block all the systemic activities of histamine [, , ]so the activation of the H2 receptor is likely to contribute to the increased vascular permeability prompted by H1 receptor stimulation. Thus, a combination of H1 and H2 receptor activation contributes to nasal airway swelling and rhinorrhea [].
The human CELF family has six members, which can be divided into two subfamilies based on their phylogeny: CELF1-2 and CELF3-6. This entry represents the RNA recognition motif 2 (RRM2) of CELF-1 and CELF-2 protein. CELF-1 and CELF-2 belong to the CELF (CUGBP and ETR-3 Like Factor)/Bruno-like protein family, whose members play important roles in the regulation of alternative splicing and translation. CELF-1 and CELF-2 share sequence similarity to the Drosophila Bruno protein and binds to the Bruno response elements (cis-acting sequences in the 3'-untranslated region (UTR) ofoskar mRNA) [].The human CELF-1 (also known as CUG-BP or BRUNOL-2) binds to RNA substrates and recruits PARN deadenylase []. It preferentially targets UGU-rich mRNA elements []. CELF-1 has been implicated in onset of type 1 myotonic dystrophy (DM1), a neuromuscular disease associated with an unstable CUG triplet expansion in the 3'-UTR (3'-untranslated region) of the DMPK (myotonic dystrophy protein kinase) gene [, ]. CELF-1 contain three highly conserved RNA recognition motifs (RRMs): two consecutive RRMs (RRM1 and RRM2) situated in the N-terminal region followed by a linker region and the third RRM (RRM3) close to the C terminus of the protein. The Xenopus homologue of CELF-1 is EDEN-BP (embryo deadenylation element-binding protein), which mediates sequence-specific deadenylation of Eg5 mRNA. It binds specifically to the EDEN motif in the 3'-untranslated regions of maternal mRNAs and targets these mRNAs for deadenylation and translational repression []. The two N-terminal RRMs of EDEN-BP are necessary for the interaction with EDEN as well as a part of the linker region (between RRM2 and RRM3). Oligomerization of EDEN-BP is required for specific mRNA deadenylation and binding []. CELF-2 (also known as CUGBP2 or ETR-3) shares high sequence identity with CELF-1, but shows different binding specificity; it binds preferentially to sequences with UG repeats and UGUU motifs. It also binds to the 3'-UTR of cyclooxygenase-2 messages, affecting both translation and mRNA stability, and binds to apoB mRNA, regulating its C to U editing []. CELF-2 also contains three highly conserved RRMs. It binds to RNA via the first two RRMs, which are also important for localization in the cytoplasm. The splicing activation or repression activity of CELF-2 on some specific substrates is mediated by RRM1/RRM2. Both, RRM1 and RRM2 of CELF-2, can activate cardiac troponin T (cTNT) exon 5 inclusion. In addition, CELF-2 possesses a typical arginine and lysine-rich nuclear localization signal (NLS) in the C terminus, within RRM3 [].
The human CELF family has six members, which can be divided into two subfamilies based on their phylogeny: CELF1-2 and CELF3-6. This entry represents the RNA recognition motif 3 (RRM3) of CELF-1 andCELF-2 protein. CELF-1 and CELF-2 belong to the CELF (CUGBP and ETR-3 Like Factor)/Bruno-like protein family, whose members play important roles in the regulation of alternative splicing and translation. CELF-1 and CELF-2 share sequence similarity to the Drosophila Bruno protein and binds to the Bruno response elements (cis-acting sequences in the 3'-untranslated region (UTR) ofoskar mRNA) [].The human CELF-1 (also known as CUG-BP or BRUNOL-2) binds to RNA substrates and recruits PARN deadenylase []. It preferentially targets UGU-rich mRNA elements []. CELF-1 has been implicated in onset of type 1 myotonic dystrophy (DM1), a neuromuscular disease associated with an unstable CUG triplet expansion in the 3'-UTR (3'-untranslated region) of the DMPK (myotonic dystrophy protein kinase) gene [, ]. CELF-1 contain three highly conserved RNA recognition motifs (RRMs): two consecutive RRMs (RRM1 and RRM2) situated in the N-terminal region followed by a linker region and the third RRM (RRM3) close to the C terminus of the protein. The Xenopus homologue of CELF-1 is EDEN-BP (embryo deadenylation element-binding protein), which mediates sequence-specific deadenylation of Eg5 mRNA. It binds specifically to the EDEN motif in the 3'-untranslated regions of maternal mRNAs and targets these mRNAs for deadenylation and translational repression []. The two N-terminal RRMs of EDEN-BP are necessary for the interaction with EDEN as well as a part of the linker region (between RRM2 and RRM3). Oligomerization of EDEN-BP is required for specific mRNA deadenylation and binding []. CELF-2 (also known as CUGBP2 or ETR-3) shares high sequenceidentity with CELF-1, but shows different binding specificity; it binds preferentially to sequences with UG repeats and UGUU motifs. It also binds to the 3'-UTR of cyclooxygenase-2 messages, affecting both translation and mRNA stability, and binds to apoB mRNA, regulating its C to U editing []. CELF-2 also contains three highly conserved RRMs. It binds to RNA via the first two RRMs, which are also important for localization in the cytoplasm. The splicing activation or repression activity of CELF-2 on some specific substrates is mediated by RRM1/RRM2. Both, RRM1 and RRM2 of CELF-2, can activate cardiac troponin T (cTNT) exon 5 inclusion. In addition, CELF-2 possesses a typical arginine and lysine-rich nuclear localization signal (NLS) in the C terminus, within RRM3 [].
Notch cell surface receptors are large, single-pass type-1 transmembrane proteins found in a diverse range of metazoan species, from human to Caenorhabditis species. The fruit fly, Drosophila melanogaster, possesses only one Notch protein, whereas in C.elegans, two receptors have been found; by contrast, four Notch paralogues (designated N1-4) have been identified in mammals, playing both unique and redundant roles. The hetero-oligomer Notch comprises a large extracellular domain (ECD), containing 10-36 tandem Epidermal Growth Factor (EFG)-like repeats, which are involved in ligand interactions; a negative regulatory region, including three cysteine-rich Lin12-Notch Repeats (LNR); a single trans-membrane domain (TM); a small intracellular domain (ICD), which includes a RAM (RBPjk-association module) domain; six ankyrin repeats (ANK), which are involved in protein-protein interactions; and a PEST domain. Drosophila Notch also contains an OPA domain []. Notch signalling is an evolutionarily conserved pathway involved in a wide variety of developmental processes, including adult homeostasis and stem cell maintenance, cell proliferation and apoptosis []. Notch is activated by a range of ligands -the so-called DSL ligands (Delta/Seratte/LAG-2). Activation is also mediated by a sequence of proteolytic events: ligand binding leads to cleavage of Notch by ADAM proteases []at site 2 (S2) and presenilin-1/g-secretase at sites 3 (S3)and 4 (S4) [].The last cleavage releases the Notch intracellular part of the protein (NICD) from the membrane and, upon release, the NICD translocates to the nucleus where it associates with a CBF1/RBJk/Su(H)/Lag1 (CSL) family of DNA-binding proteins. The subsequent recruitment of a co-activator mastermind like (MAML1) protein []promotes transcriptional activation of Notch target genes: well established Notch targets are the Hes and Hey gene families. Aberrant Notch function and signalling has been associated with a number of human disorders, including Allagile syndrome, spondylocostal dysostosis, aortic valve disease, CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), and T-cell Acute Lympho-blastic Leukemia (T-ALL); it has also been implicated in various human carcinomas [, ]. Notch3 displays a more restrictive distribution than the rest of the Notch subtypes, being expressed predominantly in vascular smooth muscle cells, the central nervous system, certain thymocytes subsets, and in regulatory T cells [].
Indoleamine 2,3-dioxgyenase (IDO, ) [, ]is a cytosolic heme protein which, together with the hepatic enzyme tryptophan 2,3-dioxygenase, catalyses the conversion of tryptophan and other indole derivatives to kynurenines. It is widely distributed in human tissues, involved in the peripheral immune tolerance, contributing to maintain homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses [, ]. The degradative action of IDO on tryptophan leads to cell death by starvation of this essential and relatively scarce amino acid. Tryptophan shortage inhibits T lymphocytes division and accumulation of tryptophan catabolites induces T-cell apoptosis and differentiation of regulatory T-cells. IDO also acts as a suppressor of anti-tumor immunity and limits the growth of intracellular pathogens by depriving tryptophan. Elevated IDO1 expression is a hallmark of major viral infections including HIV, HBV, HCV or influenza and also of major bacteria infections []. This enzyme has also been associated to protection of the fetus from maternal immune rejection []. Indoleamine 2,3-dioxygenase from yeast (BNA2) plays a role in the cellular response to telomere uncapping []. IDO is a heme-containing enzyme of about 400 amino acids. Site-directed mutagenesis showed His346 () to be essential for haem binding, indicating that this histidine residue may be the proximal ligand. Mutation of Asp274 also compromised the ability of IDO to bind haem, suggesting that Asp274 may coordinate to heme directly as the distal ligand or is essential in maintaining the conformation of the haem pocket []. There are two IDO enzyme catalysing the same reaction, IDO1 and IDO2 which differ in their affinity for tryptophan being IDO2 affinity for tryptophan much lower than that of IDO1. 50% of Caucasians harbor polymorphisms which abolish IDO2 enzymatic activity. IDO2 is expressed in human tumors in an inactive form, thus, tryptophan degradation is entirely provided by IDO1 in these cells []. IDO2 may play a role as a negative regulator of IDO1 by competing for heme-binding with IDO1[]. ALthough low efficiency IDO2 enzymes have been conserved throughout vertebrate evolution, higher efficiency IDO1 enzymes are dispensable in many lower vertebrate lineages []. It is suggested that IDO1 may have arisen by gene duplication of a more ancient proto-IDO gene before the divergence of marsupial and eutherian (placental) mammals.Other proteins that are evolutionarily related to IDO include myoglobin from the red muscle of the archaeogastropodic molluscs, Nordotis madaka (Giant abalone) and Sulculus diversicolor [, ]. These unusual globins lack enzymatic activity but have kept the heme group.
These proteins contain a domain superfamily found in serine peptidases belonging to the MEROPS peptidase families S8 (subfamilies S8A (subtilisin) and S8B (kexin) and S53 (sedolisin), both of which are members of clan SB [].The subtilisin family is one of the largest serine peptidase families characterised to date. Over 200 subtilises are presently known, more than 170 of which with their complete amino acid sequence []. It is widespread, being found in eubacteria, archaebacteria, eukaryotes and viruses []. The vast majority of the family are endopeptidases, although there is an exopeptidase, tripeptidyl peptidase [, ]. Structures have been determined for several members of the subtilisin family: they exploit the same catalytic triad as the chymotrypsins, although the residues occur in a different order (HDS in chymotrypsin and DHS in subtilisin), but the structures show no other similarity [, ]. Some subtilisins are mosaic proteins, while others contain N- and C-terminal extensions that show no sequence similarity to any other known protein [].The proprotein-processing endopeptidases kexin, furin and related enzymesform a distinct subfamily known as the kexin subfamily (S8B). These preferentially cleave C-terminally to paired basic amino acids. Members of this subfamily can be identified by subtly different motifs around the active site [, ]. Members of the kexin subfamily, along with endopeptidases R, T and K from the yeast Tritirachium and cuticle-degrading peptidase from Metarhizium, require thiol activation. This can be attributed to the presence of a cysteine near to the active site histidine []. Only one viral member of the subtilisin family is known, a 56kDa protease from herpes virus 1, which infects the channel catfish []. Sedolisins (serine-carboxyl peptidases) are proteolytic enzymes whose fold resembles that of subtilisin; however, they are considerably larger, with the mature catalytic domains containing approximately 375 amino acids. The defining features of these enzymes are a unique catalytic triad, Ser-Glu-Asp, as well as the presence of an aspartic acid residue in the oxyanion hole. High-resolution crystal structures have now been solved for sedolisin from Pseudomonas sp. 101, as well as for kumamolisin from a thermophilic bacterium, Bacillus sp. MN-32. Mutations in the human gene leads to a fatal neurodegenerative disease [].
Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).The CXC chemokine receptors are a subfamily of chemokine receptors that specifically bind and respond to cytokines of the CXC chemokine family. There are currently seven known CXC chemokine receptors in mammals, CXCR1 through to CXCR7.This entry represents the N-terminal region of the CXC type 4 chemokine receptor. CXCR4 and its ligand stromal cell-derived factor-1 (also known as CXCL12) are essential for proper fetal development. CXCR4 is also the major coreceptor for T-tropicstrains of Human immunodeficiency virus 1, and SDF-1 inhibits HIV-1 infection. Additionally, SDF-1 and CXCR4 mediate cancer cell migration and metastasis. The N-terminal domain of most chemokine receptors is the ligand binding domain and so the N-terminal domain of CXCR4 is the binding site for SDF-1 [].
This entry represents toll-like receptors (TLRs), which are key regulators of immune responses. They recognise pathogen-associated molecular patterns (PAMPs) such as bacterial lipopeptides (TLR1/2/6), bacterial flagellin (TLR5), and lipopolysaccharide (TLR4) []. In highervertebrates, TLRs are essential not only for sensing microbes by the innate immune system, but also for inducing adaptive immune system responses mediated by B and T cells [].TLRs are expressed at the cell membrane and in subcellular compartments such as the endosome. TLRs are type-I transmembrane proteins with extracellular leucine-rich repeat (LRR) motifs and an intracellular Toll/interleukin-1 receptor (TIR) domain. Members of the TLR family contribute both to cell-cell interactions and to signalling, linking extracellular signals to specific gene-expression programmes [, ]. Binding of ligands to the extracellular domains causes rearrangement of the receptor complexes and triggers the recruitment of specific adaptor proteins to the intracellular TIR domain, leading to nuclear factor-kappa B (NF-kappaB) activation and initiation of both innate and adaptive immune responses. Signalling by TLRs involves five adaptor proteins known as MyD88, MAL, TRIF, TRAM and SARM []. TLRs form homodimers or heterodimers induced by the binding of ligands to residues in the LRRs of distinct receptor chains. In mice and humans combined there are 13 paralogous TLRs; 10 in humans and 12 in mice. TLR10 is only present in humans, and TLR11-13 are only present in mice []. This entry represents some toll-like receptors, which includes TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10.In Drosophila, the Toll receptor plays a role in development as well as immunity [, ]. Toll is a component of the extracellular signaling pathway that establishes the dorsal-ventral pathway of the embryo []. Three proteases; ndl, gd and snk process easter to create active easter. Active easter defines cell identities along the dorsal-ventral continuum by activating the Spz ligand for the Tl receptor in the ventral region of the embryo []. Toll promotes heterophilic cellular adhesion []. The Drosophila Toll receptor is essential in initiating innate immune defenses to fungi and Gram-positive bacteria in adult flies []. Spz C-106 in the hemolymph controls expression of the antifungal peptide Drosomycin (Drs) by acting as a ligand of Tl and inducing an intracellular signaling pathway [].
The membrane attack complex/perforin (MACPF) domain is conserved in bacteria, fungi, mammals and plants. It was originally identified and named as being common to five complement components (C6, C7, C8-alpha, C8-beta, and C9) and perforin. These molecules perform critical functions in innate and adaptive immunity. The MAC family proteins and perforin are known to participate in lytic pore formation. In response to pathogen infection, a sequential and highly specific interaction between the constituent elements occurs to form transmembrane channels which are known as the membrane-attack complex (MAC).Only a few other MACPF proteins have been characterised and several are thought to form pores for invasion or protection [, , ]. Examples are proteins from malarial parasites [], the cytolytic toxins from sea anemones [], and proteins that provide plant immunity [, ]. Functionally uncharacterised MACPF proteins are also evident in pathogenic bacteria such as Chlamydia spp []and Photorhabdus luminescens (Xenorhabdus luminescens) [].The MACPF domain is commonly found to be associated with other N- and C-terminal domains, such as TSP1 (see ), LDLRA (see ), EGF-like (see ),Sushi/CCP/SCR (see ), FIMAC or C2 (see ). They probably control or target MACPF function [, ]. The MACPF domain oligomerizes, undergoes conformational change, and is required for lytic activity.The MACPF domain consists of a central kinked four-stranded antiparallel beta sheet surrounded by alpha helices and beta strands, forming two structural segments. Overall, the MACPF domain hasa thin L-shaped appearance. MACPF domains exhibit limited sequence similarity but contain a signature [YW]-G-[TS]-H-[FY]-x(6)-G-G motif [, , ].Some proteins known to contain a MACPF domain are listed below:Vertebrate complement proteins C6 to C9. Complement factors C6 to C9 assemble to form a scaffold, the membrane attack complex (MAC), that permits C9 polymerisation into pores that lyse Gram-negative pathogens [, ].Vertebrate perforin. It is delivered by natural killer cells and cytotoxic T lymphocytes and forms oligomeric pores (12 to 18 monomers) in the plasma membrane of either virus-infected or transformed cells.Arabidopsis thaliana (Mouse-ear cress) constitutively activated cell death 1 (CAD1) protein. It is likely to act as a mediator that recognises plant signals for pathogen infection [].Arabidopsis thaliana (Mouse-ear cress) necrotic spotted lesions 1 (NSL1) protein [].Venomous sea anemone Phyllodiscus semoni (Night anemone) toxins PsTX-60A and PsTX-60B [].Venomous sea anemone Actineria villosa (Okinawan sea anemone) toxin AvTX-60A [].Plasmodium sporozoite microneme protein essential for cell traversal 2 (SPECT2). It is essential for the membrane-wounding activity of the sporozoite and is involved in its traversal of the sinusoidal cell layer prior to hepatocyte-infection [].P. luminescens Plu-MACPF. Although nonlytic, it was shown to bind to cell membranes [].Chlamydial putative uncharacterised protein CT153 [].
The membrane attack complex/perforin (MACPF) domain is conserved in bacteria, fungi, mammals and plants. It was originally identified and named as being common to five complement components (C6, C7, C8-alpha, C8-beta, and C9) and perforin. These molecules perform critical functions in innate and adaptive immunity. The MAC family proteins and perforin are known to participate in lytic pore formation. In response to pathogen infection, a sequential and highly specific interaction between the constituent elements occurs to form transmembrane channels which are known as the membrane-attack complex (MAC).Only a few other MACPF proteins have been characterised and several are thought to form pores for invasion or protection [, , ]. Examples are proteins from malarial parasites [], the cytolytic toxins from sea anemones [], and proteins that provide plant immunity [, ]. Functionally uncharacterised MACPF proteins are also evident in pathogenic bacteria such as Chlamydia spp []and Photorhabdus luminescens (Xenorhabdus luminescens) [].The MACPF domain is commonly found to be associated with other N- and C-terminal domains, such as TSP1 (see ), LDLRA (see ), EGF-like (see ),Sushi/CCP/SCR (see ), FIMAC or C2 (see ). They probably control or target MACPF function [, ]. The MACPF domain oligomerizes, undergoes conformational change, and is required for lytic activity.The MACPF domain consists of a central kinked four-stranded antiparallel beta sheet surrounded by alpha helices and beta strands, forming two structural segments. Overall, the MACPF domain has a thin L-shaped appearance. MACPF domainsexhibit limited sequence similarity but contain a signature [YW]-G-[TS]-H-[FY]-x(6)-G-G motif [, , ].Some proteins known to contain a MACPF domain are listed below:Vertebrate complement proteins C6 to C9. Complement factors C6 to C9 assemble to form a scaffold, the membrane attack complex (MAC), that permits C9 polymerisation into pores that lyse Gram-negative pathogens [, ].Vertebrate perforin. It is delivered by natural killer cells and cytotoxic T lymphocytes and forms oligomeric pores (12 to 18 monomers) in the plasma membrane of either virus-infected or transformed cells.Arabidopsis thaliana (Mouse-ear cress) constitutively activated cell death 1 (CAD1) protein. It is likely to act as a mediator that recognises plant signals for pathogen infection [].Arabidopsis thaliana (Mouse-ear cress) necrotic spotted lesions 1 (NSL1) protein [].Venomous sea anemone Phyllodiscus semoni (Night anemone) toxins PsTX-60A and PsTX-60B [].Venomous sea anemone Actineria villosa (Okinawan sea anemone) toxin AvTX-60A [].Plasmodium sporozoite microneme protein essential for cell traversal 2 (SPECT2). It is essential for the membrane-wounding activity of the sporozoite and is involved in its traversal of the sinusoidal cell layer prior to hepatocyte-infection [].P. luminescens Plu-MACPF. Although nonlytic, it was shown to bind to cell membranes [].Chlamydial putative uncharacterised protein CT153 [].
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.Integrin Beta-2 is also referred to as ITGB2 and is known to interact with three different alpha integrin chains: ITGAL, ITGAM and ITGAX. These three integrin heterodimers are associated with leukocyte adhesion deficiency (LAD), which is characterised by recurrent bacterial infections. LFA-1 (ITGB2/ITGAL) is one of the most well studied of these integrins. Engagement of LFA-1 results in increased AP-1 dependent gene expression, which is mediated by the nuclear translocation of JAB1 []. The ligand for LFA-1 is JAM-1, a member of the endothelial immunoglobulin superfamily. JAM-1 contributes to LFA-1 dependent transendothelial migration of leukocytes and LFA-1 mediated arrest of T cells []. Studies of marginal zone (MZ) B cells also showed that LFA-1, together with alpha4beta1, is required for localisation of those cells in the splenic MZ and that these integrins are necessary for lymphoid tissue compartmentalization [].
The only CX3C chemokine identified to date is CX3C chemokine ligand 1 (CX3CL1), also known as fractalkine or neurotactin. With its unique CX3CR1 receptor [], it is involved in adherence to the endothelium of the inflammatory monocyte population [].CX3CL1 and CXCL16 represent two exceptions among the members of the chemokine family. In addition to their chemokine domain, they possess three other domains: a mucin-like stalk, a transmembrane (TM) domain, and a cytosolic tail [, ]. When interacting with their cognate receptors (CX3CR1 and CXCR6, respectively), these chemokines induce cell-cell adhesion []. CX3CL1 and CXCL16 can also be cleaved by metalloproteinases to yield a soluble form that is chemotactic [, ]. CX3CL1 also binds and activates integrins through its chemokine domain in a CX3CR1-dependent and independent manner, binding to the classical ligand-binding site (RGD-binding site, site 1) or to a second site (site 2) in integrins, respectively [].Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions,and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).
This superfamily represents the tryptophan and indoleamine 2,3-dioxygenase.Tryptophan 2,3-dioxygenase () enzymes are involved in tryptophan metabolism, which catalyses the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring [].Indoleamine 2,3-dioxgyenase (IDO, ) [, ]is a cytosolic heme protein which, together with the hepatic enzyme tryptophan 2,3-dioxygenase, catalyses the conversion of tryptophan and other indole derivatives to kynurenines. It is widely distributed in human tissues, involved in the peripheral immune tolerance, contributing to maintain homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses [, ]. The degradative action of IDO on tryptophan leads to cell death by starvation of this essential and relatively scarce amino acid. Tryptophan shortage inhibits T lymphocytes division and accumulation of tryptophan catabolites induces T-cell apoptosis and differentiation of regulatory T-cells. IDO also acts as a suppressor of anti-tumor immunity and limits the growth of intracellular pathogens by depriving tryptophan. Elevated IDO1 expression is a hallmark of major viral infections including HIV, HBV, HCV or influenza and also of major bacteria infections []. This enzyme has also been associated to protection of the fetus from maternal immune rejection []. Indoleamine 2,3-dioxygenase from yeast (BNA2) plays a role in the cellular response to telomere uncapping []. IDO is a heme-containing enzyme of about 400 amino acids. Site-directed mutagenesis showed His346 () to be essential for haem binding, indicating that this histidine residue may be the proximal ligand. Mutation of Asp274 also compromised the ability of IDO to bind haem, suggesting that Asp274 may coordinate to heme directly as the distal ligand or is essential in maintaining the conformation of the haem pocket []. There are two IDO enzyme catalysing the same reaction, IDO1 and IDO2 which differ in their affinity for tryptophan being IDO2 affinity for tryptophan much lower than that of IDO1. 50% of Caucasians harbor polymorphisms which abolish IDO2 enzymatic activity. IDO2 is expressed in human tumors in an inactive form, thus, tryptophan degradation is entirely provided by IDO1 in these cells []. IDO2 may play a role as a negative regulator of IDO1 by competing for heme-binding with IDO1[]. ALthough low efficiency IDO2 enzymes have been conserved throughout vertebrate evolution, higher efficiency IDO1 enzymes are dispensable in many lower vertebrate lineages []. It is suggested that IDO1 may have arisen by gene duplication of a more ancient proto-IDO gene before the divergence of marsupial and eutherian (placental) mammals.Other proteins that are evolutionarily related to IDO include myoglobin from the red muscle of the archaeogastropodic molluscs, Nordotis madaka (Giant abalone) and Sulculus diversicolor [, ]. These unusual globins lack enzymatic activity but have kept the heme group.
This entry represents the C-terminal conserved domain found in caspases mostly from animals. This domain includes the core of p45 (45kDa) precursor of caspases, which can be processed to produce the active p20 (20kDa) and p10 (10kDa) subunits. Caspases (Cysteine-dependent ASPartyl-specific proteASE) are cysteine peptidases that belong to the MEROPS peptidase family C14 (caspase family, clan CD) based on the architecture of their catalytic dyad or triad []. Caspases from animals can be classified as C14A subfamiy. Caspases are tightly regulated proteins that require zymogen activation to become active, and once active can be regulated by caspase inhibitors. Activated caspases act as cysteine proteases, using the sulphydryl group of a cysteine side chain for catalysing peptide bond cleavage at aspartyl residues in their substrates. The catalytic cysteine and histidine residues are on the p20 subunit after cleavage of the p45 precursor.Caspases are mainly involved in mediating cell death (apoptosis) [, , ]. They have two main roles within the apoptosis cascade: as initiators that trigger the cell death process, and as effectors of the process itself. Caspase-mediated apoptosis follows two main pathways, one extrinsic and the other intrinsic or mitochondrial-mediated. The extrinsic pathway involves the stimulation of various TNF (tumour necrosis factor) cell surface receptors on cells targeted to die by various TNF cytokines that are produced by cells such as cytotoxic T cells. The activated receptor transmits the signal to the cytoplasm by recruiting FADD, which forms a death-inducing signalling complex (DISC) with caspase-8. The subsequent activation of caspase-8 initiates the apoptosis cascade involving caspases 3, 4, 6, 7, 9 and 10. The intrinsic pathway arises from signals that originate within the cell as a consequence of cellular stress or DNA damage. The stimulation or inhibition of different Bcl-2 family receptors results in the leakage of cytochrome c from the mitochondria, and the formation of an apoptosome composed of cytochrome c, Apaf1 and caspase-9. The subsequent activation of caspase-9 initiates the apoptosis cascade involving caspases 3 and 7, among others. At the end of the cascade, caspases act on a variety of signal transduction proteins, cytoskeletal and nuclear proteins, chromatin-modifying proteins, DNA repair proteins and endonucleases that destroy the cell by disintegrating its contents, including its DNA. The different caspases have different domain architectures depending upon where they fit into the apoptosis cascades, however they all carry the catalytic p10 and p20 subunits.Caspases can have roles other than in apoptosis, such as caspase-1 (interleukin-1 beta convertase) (), which is involved in the inflammatory process. The activation of apoptosis can sometimes lead to caspase-1 activation, providing a link between apoptosis and inflammation, such as during the targeting of infected cells. Caspases may also be involved in cell differentiation [].
Vav acts as a guanosine nucleotide exchange factor (GEF) for Rho/Rac proteins. They control processes including T cell activation, phagocytosis, and migration of cells. The Vav subgroup of Dbl GEFs consists of three family members (Vav1, Vav2, and Vav3) in mammals []. Vav1 is preferentially expressed in the hematopoietic system, while Vav2 and Vav3 are described by broader expression patterns []. Mammalian Vav proteins consist of a calponin homology (CH) domain, an acidic region, a catalytic Dbl homology (DH) domain, a PH domain, a zinc finger cysteine rich domain (C1/CRD), and an SH2 domain, flanked by two SH3 domains. In invertebrates such as Drosophila and C. elegans, Vav is missing the N-terminal SH3 domain. The DH domain is involved in RhoGTPase recognition and selectivity and stimulates the reorganization of the switch regions for GDP/GTP exchange []. The PH domain is implicated in directing membrane localization, allosteric regulation of guanine nucleotide exchange activity, and as a phospholipid-dependent regulator of GEF activity []. Vavs bind RhoGTPases including Rac1, RhoA, and RhoG, while other members of the GEF family are specific for a single RhoGTPase. This promiscuity is thought to be a result of its CRD [].PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner []. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity[]. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane []. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes [].
Major histocompatibility complex (MHC) class I molecules present antigenic peptides to CD8 T cells. The majority of peptides found associated with class I molecules are derived from nuclear and cytosolic proteins, and they are generated largely by the proteasome complex. These peptides are transported from cytosol into the lumen of the endoplasmic reticulum (ER) by a peptide transporter, which is known as the transporter associated with antigen processing (TAP). TAP is a trimeric complex consisting of TAP1, TAP2 and tapasin (TAP-A). TAP1 and TAP2 are required for peptide transport. Tapasin, which actually serves as a docking site on the TAP complex specific for interaction with class I MHC molecules, is essential for peptide loading (up to four MHC class I-tapasin complexes have beenfound to bind to each TAP molecule). However, since the exact mechanisms oftapasin functions are still unknown, it has also been speculated thattapasin may regulate the MHC class I release from the ER rather than directly loading peptides onto MHC class I molecules [, , , ].In studies of the interaction between MHC class I and TAP, it was found that TAP1, but not TAP2, is required for the association of TAP with class I molecules. Because tapasin is essential for the association of MHC class I to TAP, tapasin may directly interact with TAP1. Thus the predicted order of interaction between different molecules in the TAP complex is TAP2 to TAP1, TAP1 to tapasin, and tapasin to MHC class I molecules. Thus, by these linked events, the translocation and loading of peptides rapidly and efficientlyproceed in the same microenvironment [, ].Tapasin is a type I transmembrane (TM) glycoprotein with a double lysinemotif that is thought to be involved with mediating the retrieval of proteins back from the cis-Golgi, thus maintaining membrane proteins in theER []. It is encoded by an MHC-linked gene and is a member of theimmunoglobulin superfamily. Binding to TAP is mediated by the C-terminalregion, whereas its N-terminal 50 residues constitute the key element thatconverts the MHC class I molecules and TAP weak interactions into a stablecomplex [, ].
Interleukin-1 alpha and interleukin-1 beta (IL-1 alpha and IL-1 beta) are cytokines that participate in the regulation of immune responses, inflammatory reactions, and hematopoiesis []. Two types of IL-1 receptor, each with three extracellular immunoglobulin (Ig)-like domains, limited sequence similarity (28%) and different pharmacological characteristics have been cloned from mouse and human cell lines: these have been termed type I and type II receptors []. The receptors both exist in transmembrane (TM) and soluble forms: the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors.Both IL-1 receptors appear to be well conserved in evolution, and map to thesame chromosomal location []. The receptors can both bind all three forms of IL-1 (IL-1 alpha, IL-1 beta and IL-1RA).The crystal structures of IL1A and IL1B []have been solved, showing them to share the same 12-stranded β-sheet structure as both the heparin binding growth factors and the Kunitz-type soybean trypsin inhibitors []. The β-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel β-barrel. Several regions, especially the loop between strands 4 and 5, have been implicated in receptor binding.The Vaccinia virus genes B15R and B18R each encode proteins with N-terminal hydrophobic sequences, possible sites for attachment of N-linked carbohydrate and a short C-terminal hydrophobic domain []. These propertiesare consistent with the mature proteins being either virion, cell surface or secretory glycoproteins. Protein sequence comparisons reveal that the gene products are related to each other (20% identity) and to the Ig superfamily. The highest degree of similarity is to the human and murine interleukin-1 receptors, although both proteins are related to a wide range of Ig superfamily members, including the interleukin-6 receptor. A novel method for virus immune evasion has been proposed in which the product of one or both of these proteins may bind interleukin-1 and/or interleukin-6, preventing these cytokines reaching their natural receptors []. A similar gene product from Cowpox virus (CPV) has also been shown to specifically bind murine IL-1 beta [].This entry represents Interleukin-1 receptor, type II, the mature type II IL-1 receptor consists of (i) a ligand binding portion comprising three Ig-like domains; (ii) a single TM domain; and (iii) a short cytoplasmic domain of 29 amino acids []. This contrasts with the ~215 amino acid cytoplasmic domain of the type I receptor, suggesting that the two IL-1 receptors may interact with different signal transduction pathways. The type II receptor is expressed in a number of different tissues, including both B and T lymphocytes, and can be induced in several cell types by treatment with phorbol ester. Both IL-1 receptors appear to be well conserved in evolution, and map to the same chromosomal location. Like the type I receptor, the human type II IL-1 receptor can bind all three forms of IL-1 (IL-1 alpha, IL-1 beta and IL-1RA) [].
The variable portion of the genes encoding immunoglobulins and T cell receptors are assembled from component V, D, and J DNA segments by a site-specific recombination reaction termed V(D)J recombination. V(D)J recombination is targeted to specific sites on the chromosome by recombination signal sequences (RSSs) that flank antigen receptor gene segments. The RSS consists of a conserved heptamer (consensus, 5'-CACAGTG-3') and nonamer (consensus, 5'-ACAAAAACC-3') separated by a spacer of either 12 or 23 bp. Efficient recombination occurs between a 12-RSS and a 23-RSS, a restriction known as the 12/23 rule.V(D)J recombination can be divided into two phases, DNA cleavage and DNA joining. DNA cleavage requires two lymphocyte-specific factors, theproducts of the recombination activating genes, RAG1 and RAG2, which together recognise the RSSs and create double strand breaks at the RSS-coding segment junctions []. RAG-mediated DNA cleavage occurs in a synaptic complex termed the paired complex, which is constituted from two distinct RSS-RAG complexes, a 12-SC and a 23-SC (where SC stands for signal complex). The DNA cleavage reaction involves two distinct enzymatic steps, initial nicking that creates a 3'-OH between a coding segment and its RSS, followed by hairpin formation in which the newly created 3'-OH attacks a phosphodiester bond on the opposite DNA strand. This generates ablunt, 5' phosphorylated signal end containing all of the RSS elements, and a covalently sealed hairpin coding end. The second phase of V(D)J recombination, in which broken DNA fragments are processed and joined, is less well characterised. Signal ends are typically joinedprecisely to form a signal joint, whereas joining of the coding ends requires the hairpin structure to be opened and typically involves nucleotide addition and deletionbefore formation of the coding joint. The factors involved in these processes include ubiquitously expressed proteins involved in the repair of DNA double strandbreaks by nonhomologous end joining, terminal deoxynucleotidyl transferase, and Artemis protein.In addition to their critical roles in RSS recognition and DNA cleavage, the RAG proteins may perform two distinct types of functions in thepostcleavage phase of V(D)J. A structural function has been inferredfrom the finding that, after DNA cleavage in vitro, the DNA ends remain associated with the RAG proteins in a "four end"complex known as the cleaved signalcomplex. After release of the coding ends in vitro, and after coding joint formation in vivo, the RAG proteins remain in astable signal end complex (SEC) containing the two signal ends. These postcleavage complexes may serveas essential scaffolds for the second phase of the reaction, with the RAG proteins acting to organise the DNA processing and joining events. The second type of RAG protein-mediated postcleavage activity is the catalysis of phosphodiester bond hydrolysis and strand transfer reactions. The RAG proteins are capable of opening hairpin coding ends in vitro. The RAG proteinsalso show 3' flap endonuclease activity that may contribute to coding end processing/joining and can utilise the3' OH group on the signal ends to attack hairpin coding ends (forming hybrid or open/shut joints) or virtually any DNA duplex (forming a transposition product).
This group of sequences represent the p45 (45kDa) precursor of caspases, which can be processed to produce the active p20 (20kDa) and p10 (10kDa) subunits. Caspases (Cysteine-dependent ASPartyl-specific proteASE) are cysteine peptidases that belong to the MEROPS peptidase family C14 (caspase family, clan CD) based on the architecture of their catalytic dyad or triad []. Caspases are tightly regulated proteins that require zymogen activation to become active, and once active can be regulated by caspase inhibitors. Activated caspases act as cysteine proteases, using the sulphydryl group of a cysteine side chain for catalysing peptide bond cleavage at aspartyl residues in their substrates. The catalytic cysteine and histidine residues are on the p20 subunit after cleavage of the p45 precursor.Caspases are mainly involved in mediating cell death (apoptosis) [, , ]. They have two main roles within the apoptosis cascade: as initiators that trigger the cell death process, and as effectors of the process itself. Caspase-mediated apoptosis follows two main pathways, one extrinsic and the other intrinsic or mitochondrial-mediated. The extrinsic pathway involves the stimulation of various TNF (tumour necrosis factor) cell surface receptors on cells targeted to die by various TNF cytokines that are produced by cells such as cytotoxic T cells. The activated receptor transmits the signal to the cytoplasm by recruiting FADD, which forms a death-inducing signalling complex (DISC) with caspase-8. The subsequent activation of caspase-8 initiates the apoptosis cascade involving caspases 3, 4, 6, 7, 9 and 10. The intrinsic pathway arises from signals that originate within the cell as a consequence of cellular stress or DNA damage. The stimulation or inhibition of different Bcl-2 family receptors results in the leakage of cytochrome c from the mitochondria, and the formation of an apoptosome composed of cytochrome c, Apaf1 and caspase-9. The subsequent activation of caspase-9 initiates the apoptosis cascade involving caspases 3 and 7, among others. At the end of the cascade, caspases act on a variety of signal transduction proteins, cytoskeletal and nuclear proteins, chromatin-modifying proteins, DNA repair proteins and endonucleases that destroy the cell by disintegrating its contents, including its DNA. The different caspases have different domain architectures depending upon where they fit into the apoptosis cascades, however they all carry the catalytic p10 and p20 subunits.Caspases can have roles other than in apoptosis, such as caspase-1 (interleukin-1 beta convertase) (), which is involved in the inflammatory process. The activation of apoptosis can sometimes lead to caspase-1 activation, providing a link between apoptosis and inflammation, such as during the targeting of infected cells. Caspases may also be involved in cell differentiation [].There are non-peptidase homologues in the caspase family, such as CASP8 and FADD-like apoptosis regulator (CASH/c-FLIP), which suppresses death receptor induced apoptosis and TCR activation induced cell death by inhibiting caspase-8 activation [, , ].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Vasoactive intestinal polypeptide (VIP) has a wide physiological profile.In the periphery, it induces relaxation in smooth muscle; inhibitssecretion in certain tissues, but stimulates secretion in others; andmodulates activity of cells in the immune system. In the CNS, it has arange of both excitatory and inhibitory actions. VIP receptors aredistributed widely in the periphery, and occur throughout the gastrointestinal tract and genitourinary system, other smooth muscles andsecretory glands. In the CNS, they are found abundantly in, e.g. the cortex,hippocampus and thalamus. All VIP receptors activate adenylyl cyclase.There are two structurally distinct receptors that recognise VIP peptidesand pituitary adenylate cyclase activating polypeptide (PACAP) with similaraffinities (PACAP/VIPR-1, PACAP/VIPR-2), as well as a specific receptor forthe PACAP peptide (PACAP-1). RNA transcripts for all three receptor typesare found in human heart, brain and adipose tissue []. VIPR-1 isconstitutively expressed, while the expression of VIPR-2 is induced onlyfollowing stimulation through the TCR-associated CD3 complex []. VIPinduces the expression of the VIPR-2 gene in the absence of additionalstimuli. Differential expression and regulation of the two VIP receptorsin T lymphocytes suggests different physiological roles in mediating theimmunomodulatory activities of VIP and related neuropeptides []. PACAP type I receptors arepresent in the hypothalamus and anterior pituitary, where they regulate therelease of adrenocorticotropin, luteinising hormone, growth hormone andprolactin, and in the adrenal medulla, where they regulate the release ofepinephrine []. The receptors are also found in high concentrations intesticular germ cells, where they may regulate spermatogenesis, and in sometransformed cell lines, such as the rat pancreatic acinar carcinoma cellAR4-2J [].This entry represents VIPR-2.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionaryrelationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Vasoactive intestinal polypeptide (VIP) has a wide physiological profile.In the periphery, it induces relaxation in smooth muscle; inhibitssecretion in certain tissues, but stimulates secretion in others; andmodulates activity of cells in the immune system. In the CNS, it has arange of both excitatory and inhibitory actions. VIP receptors aredistributed widely in the periphery, and occur throughout the gastrointestinal tract and genitourinary system, other smooth muscles andsecretory glands. In the CNS, they are found abundantly in, e.g. the cortex,hippocampus and thalamus. All VIP receptors activate adenylyl cyclase.There are two structurally distinct receptors that recognise VIP peptidesand pituitary adenylate cyclase activating polypeptide (PACAP) with similaraffinities (PACAP/VIPR-1, PACAP/VIPR-2), as well as a specific receptor forthe PACAP peptide (PACAP-1). RNA transcripts for all three receptor typesare found in human heart, brain and adipose tissue []. VIPR-1 isconstitutively expressed, while the expression of VIPR-2 is induced onlyfollowing stimulation through the TCR-associated CD3 complex []. VIPinduces the expression of the VIPR-2 gene in the absence of additionalstimuli. Differential expression and regulation of the two VIP receptorsin T lymphocytes suggests different physiological roles in mediating theimmunomodulatory activities of VIP and related neuropeptides []. PACAPtype I receptors arepresent in the hypothalamus and anterior pituitary, where they regulate therelease of adrenocorticotropin, luteinising hormone, growth hormone andprolactin, and in the adrenal medulla, where they regulate the release ofepinephrine []. The receptors are also found in high concentrations intesticular germ cells, where they may regulate spermatogenesis, and in sometransformed cell lines, such as the rat pancreatic acinar carcinoma cellAR4-2J [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Vasoactive intestinal polypeptide (VIP) has a wide physiological profile.In the periphery, it induces relaxation in smooth muscle; inhibitssecretion in certain tissues, but stimulates secretion in others; andmodulates activity of cells in the immune system. In the CNS, it has arange of both excitatory and inhibitory actions. VIP receptors aredistributed widely in the periphery, and occur throughout the gastrointestinal tract and genitourinary system, other smooth muscles andsecretory glands. In the CNS, they are found abundantly in, e.g. the cortex,hippocampus and thalamus. All VIP receptors activate adenylyl cyclase.There are two structurally distinct receptors that recognise VIP peptidesand pituitary adenylate cyclase activating polypeptide (PACAP) with similaraffinities (PACAP/VIPR-1, PACAP/VIPR-2), as well as a specific receptor forthe PACAP peptide (PACAP-1). RNA transcripts for all three receptor typesare found in human heart, brain and adipose tissue []. VIPR-1 isconstitutively expressed, while the expression of VIPR-2 is induced onlyfollowing stimulation through the TCR-associated CD3 complex []. VIPinduces the expression of the VIPR-2 gene in the absence of additionalstimuli. Differential expression and regulation of the two VIP receptorsin T lymphocytes suggests different physiological roles in mediating theimmunomodulatory activities of VIP and related neuropeptides []. PACAP type I receptors arepresent in the hypothalamus and anterior pituitary, where they regulate therelease of adrenocorticotropin, luteinising hormone, growth hormone andprolactin, and in the adrenal medulla, where they regulate the release ofepinephrine []. The receptors are also found in high concentrations intesticular germ cells, where they may regulate spermatogenesis, and in sometransformed cell lines, such as the rat pancreatic acinar carcinoma cellAR4-2J [].This entry represents the PACAP-1 receptor.
Bacillus subtilis produces and secretes proteases and other types of exoenzymes at the end of the exponential phase of growth []. The ones that make up this group are known as bacillopeptidase F (MEROPS identifier S08.017), encoded by bpr, a serine protease with high esterolytic activity which is inhibited by PMSF []. Bacillopeptidase F is fibrinolytic and is synthesized as a precursor, which is either activated autocatalytically or by another, unidentified B. subtilis peptidase []. Like other members of the peptidases S8 family these have a Asp/His/Ser catalytic triad similar to that found in trypsin-like proteases, but do not share their three-dimensional structure and are not homologous to trypsin. The stability of these enzymes may be enhanced by calcium, some members have been shown to bind up to 4 ions via binding sites with different affinity [].These proteins contain a domain found in serine peptidases belonging to the MEROPS peptidase families S8 (subfamilies S8A (subtilisin) and S8B (kexin) and S53 (sedolisin), both of which are members of clan SB [].The subtilisin family is one of the largest serine peptidase families characterised to date. Over 200 subtilises are presently known, more than 170 of which with their complete amino acid sequence []. It is widespread, being found in eubacteria, archaebacteria, eukaryotes and viruses []. The vast majority of the family are endopeptidases, although there is an exopeptidase, tripeptidyl peptidase [, ]. Structures have been determined for several members of the subtilisin family: they exploit the same catalytic triad as the chymotrypsins, although the residues occur in a different order (HDS in chymotrypsin and DHS in subtilisin), but the structures show no other similarity [, ]. Some subtilisins are mosaic proteins, while others contain N- and C-terminal extensions that show no sequence similarity to any other known protein [].The proprotein-processing endopeptidases kexin, furin and related enzymesform a distinct subfamily known as the kexin subfamily (S8B). These preferentially cleave C-terminally to paired basic amino acids. Members of this subfamily can be identified by subtly different motifs around the active site [, ]. Members of the kexin subfamily, along with endopeptidases R, T and K from the yeast Tritirachium and cuticle-degrading peptidase from Metarhizium, require thiol activation. This can be attributed to the presence of a cysteine near to the active site histidine []. Only one viral member of the subtilisin family is known, a 56kDa protease from herpes virus 1, which infects the channel catfish []. Sedolisins (serine-carboxyl peptidases) are proteolytic enzymes whose fold resembles that of subtilisin; however, they are considerably larger, with the mature catalytic domains containing approximately 375 amino acids. The defining features of these enzymes are a unique catalytic triad, Ser-Glu-Asp, as well as the presence of an aspartic acid residue in the oxyanion hole. High-resolution crystal structures have now been solved for sedolisin from Pseudomonas sp. 101, as well as for kumamolisin from a thermophilic bacterium, Bacillus sp. MN-32. Mutations in the human gene leads to a fatal neurodegenerative disease [].
The human CELF family has six members, which can be divided into two subfamilies based on their phylogeny: CELF1-2 and CELF3-6. This entry represents the RNA recognition motif 1 (RRM1) of CELF-1 and CELF-2 protein. CELF-1 and CELF-2 belong to the CELF (CUGBP and ETR-3 Like Factor)/Bruno-like protein family, whose members play important roles in the regulation of alternative splicing and translation. CELF-1 and CELF-2 share sequence similarity to the Drosophila Bruno protein and binds to the Bruno response elements (cis-acting sequences in the 3'-untranslated region (UTR) ofoskar mRNA) [].The human CELF-1 (also known as CUG-BP or BRUNOL-2) binds to RNA substrates and recruits PARN deadenylase []. It preferentially targets UGU-rich mRNA elements []. CELF-1 has been implicated in onset of type 1 myotonic dystrophy (DM1), a neuromuscular disease associated with an unstable CUG triplet expansion in the 3'-UTR (3'-untranslated region) of the DMPK (myotonic dystrophy protein kinase) gene [, ]. CELF-1 contain three highly conserved RNA recognition motifs (RRMs): two consecutive RRMs (RRM1 and RRM2) situated in the N-terminal region followed by a linker region and the third RRM (RRM3) close to the C terminus of the protein. The Xenopus homologue of CELF-1 is EDEN-BP (embryo deadenylation element-binding protein), which mediates sequence-specific deadenylation of Eg5 mRNA. It binds specifically to the EDEN motif in the 3'-untranslated regions of maternal mRNAs and targets these mRNAs for deadenylation and translational repression []. The two N-terminal RRMs of EDEN-BP are necessary for the interaction with EDEN as well as a part of the linker region (between RRM2 and RRM3). Oligomerization of EDEN-BP is required for specific mRNA deadenylation and binding []. CELF-2 (also known as CUGBP2 or ETR-3) shares high sequence identity with CELF-1, but shows different binding specificity; it binds preferentially to sequences with UG repeats and UGUU motifs. It also binds to the 3'-UTR of cyclooxygenase-2 messages, affecting both translation and mRNA stability, and binds to apoB mRNA, regulating its C to U editing []. CELF-2 also contains three highly conserved RRMs. It binds to RNA via the first two RRMs, which are also important for localization in the cytoplasm. The splicing activation or repression activity of CELF-2 on some specific substrates is mediated by RRM1/RRM2. Both, RRM1 and RRM2 of CELF-2, can activate cardiac troponin T (cTNT) exon 5 inclusion. In addition, CELF-2 possesses a typical arginine and lysine-rich nuclear localization signal (NLS) in the C terminus, within RRM3 [].Proteins containing this motif also include Drosophila melanogaster Bruno protein, which plays a central role in regulation ofOskar (Osk) expression in flies. It mediates repression by binding to regulatory Bruno response elements (BREs) in the Osk mRNA 3' UTR []. The full-length Bruno protein contains three RRMs, two located in the N-terminal half of the protein and the third near the C terminus, separated by a linker region.
Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interactionwith their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).This entry represents the Duffy antigen/chemokine receptor, DARC (Duffy Antigen for Chemokines). It is also known as Fy protein [, ], and was originally identified as a blood group antigen. DARC has been found to act as a multi-specific receptor for chemokines of both the C-C and C-X-C families including CCL2, CCL5, CXCL1 and CXCL4 [, , , , ], it has also been shown to internalise chemokines but not scavenge them []. Although DARC is a 7-transmembrane protein, sharing a high content of α-helical secondary structure typical of chemokine structures [], the characteristic rhodopsin-like signature is virtually absent. As a result, unlike classical chemokine receptors DARC does not signal through G-proteins, so is regarded as an atypical chemokine receptor. DARC was initially described on red blood cells, but subsequent studies have demonstrated DARC protein expression on renal endothelial and epithelial cells and in Purkinje cells of the cerebellum, even in Duffy-negative individuals whose red cells lack DARC [, , , , ]. DARC is believed to play an important role in endothelial cells, since expression on these cell types is highly conserved, whereas the function on RBCs appears to be dispensable in order to confer resistance to malaria []. There is evidence suggesting a role for DARC in neutrophil migration from the blood into the tissues []and in modulating inflammatory response [, , , , ].
Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates [, , , , ]. Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few []. Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target. This entry represents the zinc finger domain found in the large T-antigen (T-Ag) as the D1 domain. The T-Ag is found in a group of polyomaviruses consisting of the homonymous murine virus (Py) as well as other representative members such as the Simian virus 40 (SV40) and the human BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV) []. Their large T antigen (T-Ag) protein binds to and activates DNA replication from the origin of DNA replication (ori). Insofar as is known, the T-Ag binds to the origin first as a monomer to its pentanucleotide recognition element. The monomers are then thought to assemble into hexamers and double hexamers, which constitute the form that is active in initiation of DNA replication. When bound to the ori, T-Ag double hexamers encircle DNA []. T-Ag is a multi-domain protein that contains an N-terminal J domain, a central origin-binding domain (OBD), and a C-terminal superfamily 3 helicase domain []. The helicase domain actually contains three distinct structural domains: D1 (domain 1), D2 and D3. D1 is the Zn domain at the N terminus and contains five α-helices (alpha1-alpha5). The Zn atom coordinated by a Zn motif is important in holding alpha3 (α-helix 3) and alpha4 together, which in turn provide an anchor for alpha1 and alpha2. The beginning of alpha5 packs with alpha1 and alpha2 of D1, but its C terminus extends to alpha6 of D3. The D2 domain contains three conserved helicase motifs related to SF3 helicases, namely the modified version of Walker A and B motifs and motif C. D2 folds into a core β-sheet consisting of five parallel β-strands sandwiched by α-helices. The third domain, D3, is all α-helical. Its seven α-helices originate from both the N-terminal region (alpha6-alpha8) and the C terminus (alpha13-alpha16), with D2 inserted between [].The Zn motif of T-Ag was proposed to form a canonical zinc-finger structure for DNA binding. However, the Zn domain (D1) has a globular fold stabilised by the coordination of a Zn atom through the Zn motif, and no classical zinc-finger structure specialised for DNA binding is present. The Zn motif is not directly involved in binding DNA but is instead important for stabilising the Zn-domain structure [].
Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates [, , , , ]. Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few []. Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target. This entry represents the zinc finger domain superfamily found in the large T-antigen (T-Ag) as the D1 domain. The T-Ag is found in a group of polyomaviruses consisting of the homonymous murine virus (Py) as well as other representative members such as the Simian virus 40 (SV40) and the human BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV) []. T-antigen and replication protein E1 share the same domain architecture and functionality despite low sequence similarity []. Their large T antigen (T-Ag) protein binds to and activates DNA replication from the origin of DNA replication (ori). Insofar as is known, the T-Ag binds to the origin first as a monomer to its pentanucleotide recognition element. The monomers are then thought to assemble into hexamers and double hexamers, which constitute the form that is active in initiation of DNA replication. When bound to the ori, T-Ag double hexamers encircle DNA []. T-Ag is a multi-domain protein that contains an N-terminal J domain, a central origin-binding domain (OBD), and a C-terminal superfamily 3 helicase domain []. The helicase domain actually contains three distinct structural domains: D1 (domain 1), D2 and D3. D1 is the Zn domain at the N terminus and contains five α-helices (α1-α5). The Zn atom coordinated by a Zn motif is important in holding α3 (α-helix 3) and α4 together, which in turn provide an anchor for α1 and α2. The beginning of α5 packs with α1 and α2 of D1, but its C terminus extends to α6 of D3. The D2 domain contains three conserved helicase motifs related to SF3 helicases, namely the modified version of Walker A and B motifs and motif C. D2 folds into a core β-sheet consisting of five parallel β-strands sandwiched by α-helices. The third domain, D3, is all α-helical. Its seven α-helices originate from both the N-terminal region (α6-α8) and the C terminus (α13-α16), with D2 inserted between [].The Zn motif of T-Ag was proposed to form a canonical zinc-finger structure for DNA binding. However, the Zn domain (D1) has a globular fold stabilised by the coordination of a Zn atom through the Zn motif, and no classical zinc-finger structure specialised for DNA binding is present. The Zn motif is not directly involved in binding DNA but is instead important for stabilising the Zn-domain structure [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Vasoactive intestinal polypeptide (VIP) has a wide physiological profile.In the periphery, it induces relaxation in smooth muscle; inhibitssecretion in certain tissues, but stimulates secretion in others; andmodulates activity of cells in the immune system. In the CNS, it has arange of both excitatory and inhibitory actions. VIP receptors aredistributed widely in the periphery, and occur throughout the gastrointestinal tract and genitourinary system, other smooth muscles andsecretory glands. In the CNS, they are found abundantly in, e.g. the cortex,hippocampus and thalamus. All VIP receptors activate adenylyl cyclase.There are two structurally distinct receptors that recognise VIP peptidesand pituitary adenylate cyclase activating polypeptide (PACAP) with similaraffinities (PACAP/VIPR-1, PACAP/VIPR-2), as well as a specific receptor forthe PACAP peptide (PACAP-1). RNA transcripts for all three receptor typesare found in human heart, brain and adipose tissue []. VIPR-1 isconstitutively expressed, while the expression of VIPR-2 is induced onlyfollowing stimulation through the TCR-associated CD3 complex []. VIPinduces the expression of the VIPR-2 gene in the absence of additionalstimuli. Differential expression and regulation of the two VIP receptorsin T lymphocytes suggests different physiological roles in mediating theimmunomodulatory activities of VIP and related neuropeptides []. PACAP type I receptors arepresent in the hypothalamus and anterior pituitary, where they regulate therelease of adrenocorticotropin, luteinising hormone, growth hormone andprolactin, and in the adrenal medulla, where they regulate the release ofepinephrine []. The receptors are also found in high concentrations intesticular germ cells, where they may regulate spermatogenesis, and in sometransformed cell lines, such as the rat pancreatic acinar carcinoma cellAR4-2J [].This entry represents VIPR-1.
