This entry represent the RNA recognition motif (RRM) of RCAN1.Calcipressin-1 (RCAN1, also known as DSCR1) is a calcineurin inhibitor that inactivates nuclear factor of activated T cells (NFATc) activity []. It is expressed in the primitive ventricle of the heart and during neurogenesis []. It is a phosphoprotein that increases its capacity to inhibit calcineurin when phosphorylated at the FLISPP motif, and this phosphorylation also controls the half-life of calcipressin 1 by accelerating its degradation []. The DSCR1 (Down syndrome critical region 1) gene is present in the region of human chromosome 21, trisomy of which is associated with congenital heart defects observed in Down syndrome [].
HOS1 is an E3 ubiquitin-protein ligase that acts as a common regulator in the signalling pathways that control flowering time [, ]. It mediates ubiquitination and subsequent proteasomal degradation of the transcription factor ICE1 under cold treatment []. In Arabidopsis, CONSTANS (CO) activates transcription of the floral integrators, FLOWERING LOCUS T (FT) and TWIN SISTER OF FT (TSF) genes, which in turn govern the flowering time []. Together with Nup96, HOS1 regulates CO protein turnover and thereby prevents precocious flowering in long-day conditions [].
The high affinity immunoglobulin epsilon receptor (IgE Fc receptor) subunit gamma associates with a variety of FcR alpha chains to form a functional signaling complex. The gamma subunit has a critical role in allowing the IgE Fc receptor to reach the cell surface and regulates several aspects of the immune response []. It has significant structural homology to CD3 zeta and the related CD3 eta subunit and can facilitate T cell receptor expression and signaling in the absence of CD3 zeta and CD3 eta [].
CD20, also known as membrane-spanning 4-domains subfamily A member 1 (MS4A1), was the first B cell differentiation antigen identified. CD20 is highly expressed by B cell lymphocytes throughout their development, but is absent on the hematopoietic stem cells []. Anti-CDC20 antibodies are commonly used for the treatment of B-cell lymphoid malignancies [].The function of CD20 remains unclear. It may be involved in calcium signalling downstream of B cell antigen receptor activation [, ]. CD20 has a been shown to play a central role in the generation of T cell-independent antibody responses [].
This superfamily represents the conserved region in the release factor eRF1, designated domain 2. eRF1 is involved in termination of protein biosynthesis through stop codon recognition at the A site of the ribosome and stimulation of peptidyl-tRNA bond hydrolysis at the peptidyl transferase centre []. The overall shape and dimensions of eRF1 resemble a tRNA molecule with domains 1, 2, and 3 of eRF1 corresponding to the anticodon loop, aminoacyl acceptor stem, and T stem of a tRNA molecule, respectively. The presence of the essential GGQ motif at an exposed tip of domain 2 suggests that this motif plays a direct role at the catalytic site of the peptidyl transferase centre [].
The basic structure of immunoglobulin (Ig) molecules is a tetramer of two light chains and two heavy chains linked by disulphide bonds. There are two types of light chains: kappa and lambda, each composed of a constant domain (CL) and a variable domain (VL). There are five types of heavy chains: alpha, delta, epsilon, gamma and mu, all consisting of a variable domain (VH) and three (in alpha, delta and gamma) or four (in epsilon and mu) constant domains (CH1 to CH4). Ig molecules are highly modular proteins, in which the variable and constant domains have clear, conserved sequence patterns. The domains in Ig and Ig-like molecules are grouped into four types: V-set (variable; ), C1-set (constant-1; ), C2-set (constant-2; ) and I-set (intermediate; ) []. Structural studies have shown that these domains share a common core Greek-key β-sandwich structure, with the types differing in the number of strands in the β-sheets as well as in their sequence patterns [, ].Immunoglobulin-like domains that are related in both sequence and structure can be found in several diverse protein families. Ig-like domains are involved in a variety of functions, including cell-cell recognition, cell-surface receptors, muscle structure and the immune system []. Major Histocompatibility Complex (MHC) glycoproteins are heterodimeric cell surface receptors that function to present antigen peptide fragments to T cells responsible for cell-mediated immune responses. MHC molecules can be subdivided into two groups on the basis of structure and function: class I molecules present intracellular antigen peptide fragments (~10 amino acids) on the surface of the host cells to cytotoxic T cells; class II molecules present exogenously derived antigenic peptides (~15 amino acids) to helper T cells. MHC class I and II molecules are assembled and loaded with their peptide ligands via different mechanisms. However, both present peptide fragments rather than entire proteins to T cells, and are required to mount an immune response.Some of the proteins in this group are responsible for the molecular basis of the blood group antigens, surface markers on the outside of the red blood cell membrane. Most of these markers are proteins, but some are carbohydrates attached to lipids or proteins [Reid M.E., Lomas-Francis C. The Blood Group Antigen FactsBook Academic Press, London / San Diego, (1997)]. Lutheran blood group glycoprotein (B-CAM cell surface glycoprotein) (Auberger B antigen) (F8/G253 antigen) belongs to the Lutheran blood group system and is associated with Lu(a/b), Au(a/b), LU6 to LU20 antigens.
This entry represents the constant domain of the alpha chain of alpha/beta T-cell antigen receptors (TCRs). TCRs mediate antigen recognition by T lymphocytes, and are composed of alpha and beta, or gamma and delta, polypeptide chains with variable (V) and constant (C) regions. Alpha/beta TCRs recognize antigen as peptide fragments presented by major histocompatibility complex (MHC) molecules. The antigen binding site is formed by the variable domains of the alpha and beta chains, located at the N terminus of each chain [, , ]. Alpha/beta TCRs recognize antigens differently from gamma/delta TCRs.
This group contains metallopeptidases belonging to MEROPS peptidase family M20 (clan MH), subfamilies M20A and M20B; many are classified as unassigned peptidases or non-peptidase homologues.In addition to the metallopeptidases this group of sequences contain a variety of other protein families from the archaea, bacteria and eukaryota that hydrolyse substrates that share a common structure and are dependent on cobalt or zinc for their activity []. They include:glutamate acetyltransferase ()acetylornithine deacetylase (argE) ()leucoanthocyanidin dioxygenase succinyldiaminopimelate desuccinylase (dapE) ()aminoacylase-1 (ACY1), carboxypeptidase G2 (CPG2) ()vacuolar carboxypeptidase S (yscS) ()peptidase T ()Xaa-His dipeptidase ().
Calcineurin is a Ser/Thr-specific calcium and calmodulin-dependent protein phosphatase that plays an essential role in the T cell activation pathway. Calcineurin and Nuclear factor of Activated T-cell (NFAT) proteins have been shown to participate in signalling cascades that govern the development and function of the immune, nervous, cardiovascular and musculoskeletal systems []. Calcineurin is a heterodimeric protein consisting of: i) a catalytic subunit calcineurin A, which contains an active site dinuclear metal centre, and ii) a tightly associated, myristoylated, Ca(2+)-binding subunit, calcineurin B [].
The N-terminal domain of V-set and Ig domain-containing 4 (VSIG4), also referred to as CRIg or Z39Ig, belongs to the IgV family of immunoglobulin-like domains []. A predominant feature of most Ig domains is a disulfide bridge connecting the two β-sheets with a tryptophan residue packed against the disulfide bond [].V-set and Ig domain-containing 4 (VSIG4) is a strong negative regulator of T cell proliferation and IL-2 production []. It also negatively regulates macrophage activation by activating the PI3K/Akt-STAT3 pathway, leading to pyruvate dehydrogenase kinase-2 (PDK2) upregulation and subsequent phosphorylation of pyruvate dehydrogenase, which results in reduction in pyruvate/acetyl-CoA conversion, reduction in mitochondrial reactive oxygen species secretion, and macrophage inhibition [].
This entry represents the SH3 domain of PI3K (phosphoinositide-3-kinase) subunit beta (also known as subunit p85-beta). Class I PI3Ks convert PtdIns(4,5)P2 to the critical second messenger PtdIns(3,4,5)P3. Class IA PI3Ks consist of a p110 catalytic subunit bound to one of five regulatory subunits, generated by alternative splicing of three different genes: p85alpha, p85beta, and p55gamma [, ]. The p85 subunits contain the SH3, RhoGAP, and SH2 domains. They recruit the p110 subunit to the membrane, where p110 phosphorylates inositol lipids []. Vertebrates contain two p85 isoforms, alpha and beta. In addition to regulating the p110 subunit, p85beta binds CD28 and may be involved in the activation and differentiation of antigen-stimulated T cells [].
This entry represents the SH3 domain of SLAP. Src-like adapter proteins (SLAP and SLAP2) are involved in the regulation of immune cell surface expression and signaling. They negatively regulate T cell receptor signaling []and act as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke []. They contain adjacent Src homology 3 (SH3) and Src homology 2 (SH2) domains. SLAP has been shown to regulate receptor tyrosine kinase (RTK) signaling []. It also binds to the receptor tyrosine kinase Flt3 and plays a role in signal transduction downstream of Flt3 []. SLAP2 acts as a negative regulator of FLT3 signaling [].
This entry represent the DEDDh 3'-5' exonuclease domain found in RNA exonuclease 4 (REX4 or Rex4p) []. It is a DEDDh-type DnaQ-like 3'-5' exonuclease containing three conserved sequence motifs termed ExoI, ExoII and ExoIII, with a specific Hx(4)D conserved pattern at ExoIII. These motifs are clustered around the active site and contain four conserved acidic residues that serve as ligands for the two metal ions required for catalysis []. REX proteins function in the processing and maturation of many RNA species, similar to the function of Escherchia coli RNase T [].
scUBP14, also called deubiquitinating enzyme 14, glucose-induced degradation protein 6, ubiquitin thioesterase 14, or ubiquitin-specific-processing protease 14 (MEROPS identifier C19.083), is the Saccharomyces cerevisiae orthologue of human Isopeptidase T (USP5), a deubiquitinating enzyme known to bind the 29-linked polyubiquitin chains. scUBP14 has been identified as a K29-linked polyubiquitin binding protein as well. It is involved in K29-linked polyubiquitin metabolism by binding to the 29-linked Ub4 resin and serving as an internal positive control in budding yeast [, ]. Members in this family contain two tandem ubiquitin-association (UBA) domains.This entry corresponds to the UBA2 domain in Saccharomyces cerevisiae UBP14 and related proteins [].
This entry represents Src-like-adapter 2 (SLAP2).Src-like adapter proteins (SLAP and SLAP2) are involved in the regulation of immune cell surface expression and signaling. They negatively regulate T cell receptor signaling []and act as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke []. They contain adjacent Src homology 3 (SH3) and Src homology 2 (SH2) domains. SLAP has been shown to regulate receptor tyrosine kinase (RTK) signaling []. It also binds to the receptor tyrosine kinase Flt3 and plays a role in signal transduction downstream of Flt3 []. SLAP2 acts as a negative regulator of FLT3 signaling [].
This entry represents SLAP.Src-like adapter proteins (SLAP and SLAP2) are involved in the regulation of immune cell surface expression and signaling. They negatively regulate T cell receptor signaling []and act as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke []. They contain adjacent Src homology 3 (SH3) and Src homology 2 (SH2) domains. SLAP has been shown to regulate receptor tyrosine kinase (RTK) signaling []. It also binds to the receptor tyrosine kinase Flt3 and plays a role in signal transduction downstream of Flt3 []. SLAP2 acts as a negative regulator of FLT3 signaling [].
Cathepsin W (MEROPS identifier C01.037),also known as lymphopain, is a cysteine endopeptidase predominantly expressed in lymphocytes, especially cytotoxic T cells and natural killer cells []. Cathepsin W is synthesized as a zymogen with an N-terminal propeptide. The mechanism of activation, substrate specificity and role in cell killing are unknown. Knockdown experiments with RNAi have shown that cathepsin W is required for replication of influenza virus. In cells lacking cathepsin W virus particles are unable to escape from late endosomes, and this defect can be recovered only by using proteolytically active cathepsin W [].
Interleukin-18 (IL-18) is a proinflammatory cytokine that plays a key role in the activation of natural killer and T helper 1 cell responses principally by inducing interferon-gamma (IFN-gamma). Several poxvirus genes encode proteins with sequence similarity to IL-18BPs. It has been shown that vaccinia, ectromelia and cowpox viruses secrete from infected cells a soluble IL-18BP (vIL-18BP) that may modulate the host antiviral response. The expression of vIL-18BPs by distinct poxvirus genera that cause local or general viral dissemination, or persistent or acute infections in the host, emphasises the importance of IL-18 in response to viral infections [].
Tumor necrosis factor receptor superfamily member 3 (TNFRSF3, also known as lymphotoxin beta receptor, LTbetaR, CD18, TNFCR, TNFR3, D12S370, TNFR-RP, TNFR2-RP, LT-BETA-R, TNF-R-III) plays a role in lipid metabolism, immune response, programmed cell death, and in signaling during development of lymphoid and other organs [, ]. Its ligands include lymphotoxin (LT) alpha/beta membrane form (heterotrimer) and tumor necrosis factor ligand superfamily member 14 (also known as LIGHT) []. TNFRSF3 agonism by these ligands initiates canonical, as well as non-canonical nuclear factor-kappaB (NF-kappaB) signaling, and preferentially results in the translocation of p52-RELB complexes into the nucleus []. While these ligands are often expressed by T and B cells, TNFRSF3 is conspicuously absent on T and B lymphocytes and NK cells, suggesting that signaling may be unidirectional for TNFRSF3 []. Activity of this receptor has also been linked to carcinogenesis; it helps trigger apoptosis and can also lead to release of the interleukin 8 (IL8) [, ]. Alternatively spliced transcript variants encoding multiple isoforms have been observed.This entry represents the N-terminal domain of TNFRSF3. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
Calcipressin-1 (RCAN1, also known as DSCR1) is a calcineurin inhibitor that inactivates nuclear factor of activated T cells (NFATc) activity []. It is expressed in the primitive ventricle of the heart and during neurogenesis []. It is a phosphoprotein that increases its capacity to inhibit calcineurin when phosphorylated at the FLISPP motif, and this phosphorylation also controls the half-life of calcipressin 1 by accelerating its degradation []. The DSCR1 (Down syndrome critical region 1) gene is present in the region of human chromosome 21, trisomy of which is associated with congenital heart defects observed in Down syndrome [].Calcipressins (RCANs) are a novel family of calcineurin regulators that have been suggested as key factors contributing to Down syndrome in humans. Three human calcipressins have been identified, calcipressin 1-3. Calcipressin 1 is also known as modulatory calcineurin-interacting protein 1 (MCIP1), Adapt78 and Down syndrome critical region 1 (DSCR1). Calcipressin 2 is variously known as MCIP2, ZAKI-4 and DSCR1-like 1. Calcipressin 3 is also called MCIP3 and DSCR1-like 2 []. Calcipressins contain an N-terminal RNA recognition motif (RRM), a highly conserved SP repeat domain containing the phosphorylation site by GSK-3, a well-known PxIxIT motif responsible for docking many substrates to calcineurin, and a C-terminal TxxP motif [].Calcineurin is a calcium-responsive enzyme that dephosphorylates the nuclear factor of activated T cells (NFAT). In doing so, it promotes its nuclear translocation and uniquely links calcium signalling to transcriptional regulation [].
Monocarboxylate transporter 1 (MCT1), also known as SLC16A1, belongs to the MCT family. It facilitates unidirectional proton-linked transport of L-lactate across the plasma membrane [, ]. Several natural occurring substrates for MCT1 have been found, including L-lactate, pyruvate, beta-hydroxybutyrate, and acetoacetate []. Inhibition of MCT1 during T lymphocyte activation results in selective and profound inhibition of the extremely rapid phase of T cell division essential for an effective immune response. Therefore, MCT1 has been used as a target for immunosuppressive therapy [, ].Monocarboxylate transporters (MCTs) catalyse the proton-linked transport of monocarboxylates such as L-lactate, pyruvate, and the ketone bodies across the plasma membrane [, ]. All of the MCT family (also known as SLC16 solute carrier family) members share conserved sequence motifs. They are are predicted to have 12-transmembrane helices (TMs) with intracellular C and N termini and a large cytosolic loop between TMs 6 and 7. Four mammalian isoforms, MCTs 1-4, have been identified, each with distinct substrate and inhibitor affinities []. MCT1-4 have been linked to cancer maintenance and aggressiveness [].
Pseudouridine synthases catalyse the isomerisation of uridine to pseudouridine (Psi) in a variety of RNA molecules, and may function as RNA chaperones. Pseudouridine is the most abundant modified nucleotide found in all cellular RNAs. There are four distinct families of pseudouridine synthases that share no global sequence similarity, but which do share the same fold of their catalytic domain(s) and uracil-binding site and are descended from a common molecular ancestor. The catalytic domain consists of two subdomains, each of which has an α+β structure that has some similarity to the ferredoxin-like fold (note: some pseudouridine synthases contain additional domains). The active site is the most conserved structural region of the superfamily and is located between the two homologous domains. These families are [, ]:Pseudouridine synthase I, TruA.Pseudouridine synthase II, TruB, which contains and additional C-terminal PUA domain.Pseudouridine synthase RsuA. RluB, RluE and RluF are also part of this family.Pseudouridine synthase RluA. TruC, RluC and RluD belong to this family.Pseudouridine synthase TruD, which has a natural circular permutation in the catalytic domain, as well as an insertion of a family-specific α+β subdomain.TruB is responsible for the pseudouridine residue present in the T loops of virtually all tRNAs. TruB recognises the preformed 3-D structure of the T loop primarily through shape complementarity. It accesses its substrate uridyl residue by flipping out the nucleotide and disrupts the tertiary structure of tRNA [].This entry represents an N-terminal domain found in pseudouridine synthase TruB, as well as Cbf5p that modifies rRNA [].
Retinoblastoma-like and retinoblastoma-associated proteins may have a function in cell cycle regulation. They form a complex with adenovirus E1A and SV40 large T antigen, and may bind and modulate the function of certain cellular proteins with which T and E1A compete for pocket binding. The proteins may act as tumor suppressors, and are potent inhibitors of E2F-mediated trans-activation. This domain has the cyclin fold [].The crystal structure of the Rb pocket bound to a nine-residue E7 peptide containing the LxCxE motif, shared by other Rb-binding viral and cellular proteins, shows that the LxCxE peptide binds a highly conserved groove on the B-box portion of the pocket; the A-box portion (see ) appears to be required for the stable folding of the B box. Also highly conserved is the extensive A-B interface, suggesting that it may be an additional protein-binding site. The A and B boxes each contain the cyclin-fold structural motif, with the LxCxE-binding site on the B-box cyclin fold being similar to a Cdk2-binding site of cyclin A and to a TBP-binding site of TFIIB [].The A and B boxes are found at the C-terminal end of the protein; the B-box is on C-terminal side of the A-box.
Retinoblastoma-like and retinoblastoma-associated proteins may have a function in cell cycle regulation. They form a complex with adenovirus E1A and Simian virus 40 (SV40) large T antigen, and may bind and modulate the function of certain cellular proteins with which T and E1A compete for pocket binding. The proteins may act as tumor suppressors, and are potent inhibitors of E2F-mediated trans-activation. This domain has the cyclin fold [].The crystal structure of the Rb pocket bound to a nine-residue E7 peptide containing the LxCxE motif, shared by other Rb-binding viral and cellular proteins, shows that the LxCxE peptide binds a highly conserved groove on the B-box portion of the pocket; the A-box portion appears to be required for the stable folding of the B box (see ). Also highly conserved is the extensive A-B interface, suggesting that it may be an additional protein-binding site. The A and B boxes each contain the cyclin-fold structural motif, with the LxCxE-binding site on the B-box cyclin fold being similar to a Cdk2-binding site of cyclin A and to a TBP-binding site of TFIIB [].The A and B boxes are found at the C-terminal end of the protein; the A-box is on N-terminal side of the B-box.
This entry represents the multiple membrane-spanning S (specificity) component of ECF (energy coupling factor) transporters. This entry includes Lactobacillus casei FolT, which is a folate-binding protein []. Several members were found in the vicinity of the bifunctional enzyme folC, involved in making active cofactor from imported folate. However, some species have multiple members of this family, suggesting some diversity of function.ECF transporters usually contain two ATPase subunits (or a double-length fusion protein), a T component, and a substrate capture (S) component that is highly variable, and may be interchangeable in genomes with only one T component.ECF transporters can be classified into two groups: group I includes transporters that have a dedicated AT module encoded in the same gene cluster as an S component, while group II employs a universal energy-coupling module (EcfAA'T) that is encoded by a separate gene cassette and shared by many different unlinked S components. Group II is ubiquitous in the phyla Firmicutes and Thermotogales and also occurs in some members of the Archaea [].
The virion infectivity factor (vif) is an accessory protein, which is essential for HIV replication in host cells. Vif of Human immunodeficiency virus 1 (HIV-1) affects the infectivity of virus particles []to T lymphocytes and macrophages (in some casesincreasing the infectivity of HIV-1 particles by 100- to 1000-fold), but has no direct effect on transcription, translation or virus release. Vif antibodies are found in the sera of patients at all levels of HIV-1 infection, indicating that vif is expressed in natural infections in vivo. Other lentiviruses, including Simian immunodeficiency virus (SIV-cpz), Visna/Maedi virus, and Feline immunodeficiency virus (FIV), have vif open reading frames, suggestingvif plays an essential role during natural infections [].The expression of vif in BHK-21 cells has been shown to be linked to amodification of the C terminus of gp41env, which modification is inhibited by trans-epoxysuccinyl-L-leucylamido-(4-guanidio)butane (E64), a specific inhibitor of cysteine proteases []. Coupled with sequence analysis and the effects of point mutations in vif, it has been suggested that vif could be a cysteine protease. Virions produced in the absence of Vif have abnormal core morphology and those produced in primary T cells carry immature core proteins and low levels of mature capsid [].In humans, HIV-1 Vif hijacks cellular E3 ligase components containing CUL5, RBX2, ELOB, ELOC and CBFbeta, to poly-ubiquitinate antiviral cellular factors, APOBEC3 proteins [, , ]. In sheep and goats, Caprine arthritis encephalitis virus (CAEV) Vif is responsible for degradation of oaA3Z2-Z3 [].
Tumor necrosis factor receptor superfamily member 8 (TNFRSF8), also known as CD30, Ki-1 or D1S166E, is expressed by activated T and B cells. It transduces signals that lead to the activation of NF-kappaB, mediated by the adaptor proteins TRAF2 and TRAF5 []. This receptor has been shown to limit the proliferative potential of auto-reactive CD8 effector T cells and protect the body against autoimmunity []. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. CD30 is expressed in malignant Hodgkin and Reed-Sternberg cells on the surface of extracellular vesicles, facilitating CD30-CD30L interaction between cell types []. This receptor is also associated with anaplastic large cell lymphoma. It is expressed in embryonal carcinoma, but not in seminoma, making it a useful marker in distinguishing between these germ cell tumors [, ]. Since CD30 has restricted expression in normal tissues, it is an optimal target for selectively eliminating CD30-expressing neoplastic cells by specific toxin-conjugated monoclonal antibodies (mAbs) [, ].This entry represents the N-terminal domain of TNFRSF8. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
Tumor necrosis factor receptor superfamily member 5 (TNFRSF5), commonly known as CD40 and also as CDW40, p50 or Bp50, is widely expressed in diverse cell types including B lymphocytes, dendritic cells, platelets, monocytes, endothelial cells, and fibroblasts []. It is essential in mediating a wide variety of immune and inflammatory responses, including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal centre formation [, , , ]. Its natural immunomodulating ligand is CD40L, and a primary defect in the CD40/CD40L system is associated with X-linked hyper-IgM (XHIM) syndrome []. It is also involved in tumorigenesis; CD40 expression is significantly higher in gastric carcinomas and it is associated with the lymphatic metastasis of cancer cells and their tumor node metastasis (TNM) classification []. Upregulated levels of CD40/CD40L on B cells and T cells may play an important role in the immune pathogenesis of breast cancer []. Consequently, the CD40/CD40L system serves as a link between tumorigenesis, atherosclerosis, and the immune system, and offers a potential target for drug therapy for related diseases, such as cancer, atherosclerosis, diabetes mellitus, and immunological rejection [].This entry represents the N-terminal domain of TNFRSF5. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
Signal transducer and activator of transcription 4 (STAT4) transduces interleukin-12, interleukin-23, and type I interferon cytokine signals in T cells and monocytes [, ]. It plays an important role in CD4+ Th1 lineage differentiation and IFN-gamma protein expression by CD4+ T cells []. It is crucial for both innate and adaptive immune responses to viral infection []. Variations of the STAT4 gene affect the susceptibility to autoimmune diseases [], such as systemic lupus erythematosus 11 (SLEB11) []and rheumatoid arthritis (RA) []. STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are boundto cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins []. Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes []. STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 []. This entry represents the SH2 domain of STAT4.
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain- a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 1B (also known as TNF-R2 and CD120b antigen) is present on many cell types, especially those of myeloid origin, and is strongly expressed on stimulated T and B lymphocytes. It is the main TNF receptor found on circulating T cells and is the major mediator of autoregulatory apoptosis in CD8+ cells [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain - a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ].TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease [].TNF receptor 9 (also known as ILA and CD137 antigen) is expressed by activated T and B lymphocytes and monocytes. Stimulation of the receptor inhibits proliferation of activated T lymphocytes and induces programmed cell death [].
Signal transducer and activator of transcription 4 (STAT4) transduces interleukin-12, interleukin-23, and type I interferon cytokine signals in T cells and monocytes [, ]. It plays an important role in CD4+ Th1 lineage differentiation and IFN-gamma protein expression by CD4+ T cells []. It is crucial for both innate and adaptive immune responses to viral infection []. Variations of the STAT4 gene affect the susceptibility to autoimmune diseases [], such as systemic lupus erythematosus 11 (SLEB11) []and rheumatoid arthritis (RA) []. STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are bound to cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins []. Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes []. STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 [].
Nuclear factor of activated T-cells 5 (NFAT5) is a member of the nuclear factors of activated T cells (NFAT) of transcription factors. Proteins belonging to this family play a central role in inducible gene transcription during the immune response. This protein regulates gene expression induced by osmotic stress in mammalian cells. NFAT5, regulated by DDX5/DDX17, plays a role in the migratory capacity of breast cancer cells []. Unlike monomeric members of this protein family, this protein exists as a homodimer and forms stable dimers with DNA elements. Five transcript variants encoding three different isoforms have been identified for this gene [].NFAT proteins appear to be regulated primarily at the level of their subcellular localisation []. They are found exclusively in the cytoplasm of resting T cells, and consist of 2 components: a pre-existing cytoplasmic component that translocates into the nucleus on calcium mobilisation, and an inducible nuclear component comprising members of the activating protein-1 (AP-1) family of transcription factors. In response to antigen receptor signalling, the calcium-regulated phosphatase calcineurin acts directly to dephosphorylate NFAT proteins, causing their rapid translocation from the cytoplasm to the nucleus, where they cooperatively bind their target.
Caveolin-1 (CAV-1) is a structural components of caveolae, which are 50-100 nm invaginations of the plasma membrane that play various physiological roles. CAV1 associates with cavin-1 and is confined to the plasma membrane []. CAV-1 has several functions, for instance, it regulates TCR signal strength and regulatory T cell differentiation into alloreactive T cells []. It can also affect the permeability of blood-tumour barrier (BTB) by regulating the expression of tight junction-associated proteins []. Caveolae are 50-100 nm invaginations located at the plasma membrane of many cell types and are known to transport molecules across endothelial cells []. Caveolae require the caveolin proteinfor formation. Caveolins may act as scaffolding proteins within caveolar membranes by compartmentalizing and concentrating signalling molecules. Mammals have three caveolin proteins:caveolin-1 (Cav-1, or VIP21), caveolin-2 and caveolin-3 (or M-caveolin). Various classes of signalling molecules, including G-protein subunits, receptor and non-receptor tyrosine kinases, endothelial nitric oxide synthase (eNOS), and small GTPases, bind Cav-1 through its 'caveolin-scaffolding domain' [].Caveolins are proteins of about 20 Kd, they form high molecular mass homo-oligomers. Structurally they seem to have N-terminal and C-terminal hydrophilic segments and a long central transmembrane domain that probably forms a hairpin in the membrane. Both extremities are known to face the cytoplasm. Caveolae are enriched with cholesterol and Cav-1 is one of the few proteins that binds cholesterol tightly and specifically.
The egg peptide speract receptor is a transmembrane glycoprotein of about500 amino acids []. Topologically, it comprises a large extracellulardomain of about 450 residues, followed by a transmembrane domain and ashort cytoplasmic region of about 12 amino acids. The extracellulardomain contains 4 repeats of a well-conserved region, which spans 115amino acids and contains 6 conserved cysteines. A similar domain is alsofound towards the C terminus of macrophage scavenger receptor type I [],a membrane glycoprotein implicated in the pathologic deposition ofcholesterol in arterial walls during artherogenesis, and in the CD5glycoprotein, which acts as a receptor in regulating T-cell proliferation.The T1/Leu-1/CD5 glycoprotein is expressed at the surface membrane of allmature T cells. It has been implicated both in the proliferative response of activated T cells and in T-cell helper function []. Thecomplete amino-acid sequence of the T1 precursor has been deduced from cDNAclones. The protein contains a classical signal peptide; a 347-residue extracellular segment; a transmembrane region; and a 93-residue intra-cellular segment []. The extracellular region contains several cysteineresidues and comprises 2 speract receptor domains separated by a proline/threonine-rich region []. CD5 has been shown to function as a receptor,delivering co-stimulatory signals to T-cells, interacting specifically withthe cell-surface protein CD72 (Lyb-2 in mice) exclusive to B-cells [].
Glycoproteins B7-1 (CD80) and B7-2 (CD86) are expressed on antigen-presenting cells and deliver the co-stimulatory signal through CD28 and CTLA-4 (CD152) on T cells. Signalling through CD28 augments the T-cell response, whereas CTLA-4 signalling attenuates it []. The CTLA-4 and B7-2 monomers are both two-layer β-sandwiches that display the chain topology characteristic of the immunoglobulin variable (V-type) domains present in antigen receptors. The front and back sheets of B7-2 are composed of AGFCC'C"and BED strands, respectively []. Members of the IgV family are components of immunoglobulin (Ig) and T cell receptors. The basic structure of Ig molecules is a tetramer of two light chains and two heavy chains linked by disulfide bonds. In Ig, each chain is composed of one variable domain (IgV) and one or more constant domains (IgC); these names reflect the fact that the variability in sequences is higher in the variable domain than in the constant domain []. Within the variable domain, there are regions of even more variability called the hypervariable or complementarity-determining regions (CDRs) which are responsible for antigen 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 playa 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 membersof 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 10 (CCR10), previously known as G protein-coupled receptor 2 (GPR2) []. CCR10 is a receptor for CCL27 [], and CCL28 []. CCR10 is found in melanocytes [], dermal fibroblasts, dermal micro-vascular endothelial cells and has also been detected in T-cells []. It is involved in T cell-mediated skin inflammation, having been shown to recruit regulatory T cells to mucosal layers []. The receptor may also play a role in directing metastasis [].
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 expressedon 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).Chemokine XC receptor 1 (XCR1), which this entry represents is a receptor for lymphotactin []. Lymphotactin is the only known member of the C (or XC) chemokine family, and is produced by certain subsets of T cells and natural killer cells and is also chemotactic for these cell types []. XCR1 is strongly expressed in placenta and at lower levels in the spleen and thymus and detected only at very low levels in peripheral blood leukocytes []. Within these tissues, expression is restricted to CD8+ T cells and natural killer cells [, ]. Binding of lymphotactin to XCR1 stimulates calcium mobilisation and migration in a pertussis toxin-sensitive manner, indicating coupling of the receptor to Gi type proteins [, ]. The matching expression patterns of both lymphotactin and its receptor suggest a role for the chemokine in self-recruitment of leukocytes [].
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 helpercells [, ]. 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 C chemokine subfamily is composed of two members, XC chemokine ligand 1 (XCL1), also known as lymphotactin or SCM-1 alpha, and XC chemokine ligand 2 (XCL2), also known as SCM-1 beta []. The cognate receptor for these chemokines is XCR1 [].XCL1 is an inflammatory chemokine that produced by activated CD8+ T cells and natural killer cells. It is involved in the mediation of interactions between antigen-presenting dendritic cells and T-cells, and induction of CD8+ effector T-cell responses [, ]. It is also involved in the formation of self-tolerance mechanisms through the development of T regulatory cells within the thymus []. Less is known about its closely related paralogue XCL2, although the in vitro functional profiles are virtually identical []. Human XCL2 and XCL1 amino acid sequences differ at only two positions near the N terminus [].Viral XCL1 (vXCL1) exclusively binds to CD4(-) rat dendritic cells (DC), a subset of DC that express the corresponding chemokine receptor XCR1, a strategy to subvert cytotoxic immune responses [].
This entry represents the death domain (DD) found in the FS7-associated cell surface antigen (FAS). FAS, also known as TNFRSF6 (TNF receptor superfamily member 6), APT1, CD95, FAS1, or APO-1, together with FADD (Fas-associating via Death Domain) and caspase 8, is an integral part of the death inducing signalling complex (DISC), which plays an important role in the induction of apoptosis and is activated by binding of the ligand FasL to FAS [, ]. FAS also plays a critical role in self-tolerance by eliminating cell types (autoreactive T and B cells) that contribute to autoimmunity [].DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes [, ].
This family represents the tail assembly protein GT, from lambda-like viruses and their prophage.In bacteriophage lambda, the overlapping open reading frames G and T are expressed by a programmed translational frameshift to produce the tail assembly proteins G and GT []. Tail assembly protein GT shares it's N-terminal residues with tail assembly protein G, followed by residues of unique sequence []. An analogous frameshift is widely conserved among other dsDNA tailed phages in their corresponding 'G' and 'GT' tail genes even in the absence of detectable sequence homology []. The lambda tail assembly protein G and frameshift product GT are produced in a molar ratio of approximately 30:1[]. The correct molar ratio of these two related proteins, normally determined by the efficiency of the frameshift, is crucial for efficient assembly of functional tails []. Although tail assembly proteins G and GT are both required for assembly of functional tails, neither is present in mature tails [].
Flotillin is a family of lipid-membrane-associated proteins found in bacteria, archaea and eukaryotes. Flotillins in vertebrates are associated with sphingolipids and cholesterol-enriched membrane microdomains, known as lipid-rafts [, ]. These rafts, along with other membrane components, are important in cell-signalling. This entry includes flotillin-1 (also known as reggie-2), flotillin-2 (also known as reggie-1) and their homologues. They play a role in various cellular processes such as insulin signaling, T cell activation, membrane trafficking, phagocytosis, and epidermal growth factor receptor signaling []. Flotillins in other organisms have roles in viral pathogenesis, endocytosis, and membrane shaping [, ]. In bacteria, these proteins are found in membrane microdomains that may be equivalent to eukaryotic membrane rafts []. Similarly to eukaryotic flotillin proteins, flotillins in bacteria play an essential role in organizing and maintaining the correct architecture of the functional membrane microdomains []. This entry represents the C-terminal domain of flotilin-1 and flotilin-2 and its homologues.
Calcipressins (RCANs) are a novel family of calcineurin regulators that have been suggested as key factors contributing to Down syndrome in humans. Three human calcipressins have been identified, calcipressin 1-3. Calcipressin 1 is also known as modulatory calcineurin-interacting protein 1 (MCIP1), Adapt78 and Down syndrome critical region 1 (DSCR1). Calcipressin 2 is variously known as MCIP2, ZAKI-4 and DSCR1-like 1. Calcipressin 3 is also called MCIP3 and DSCR1-like 2 []. Calcipressins contain an N-terminal RNA recognition motif (RRM), a highly conserved SP repeat domain containing the phosphorylation site by GSK-3, a well-known PxIxIT motif responsible for docking many substrates to calcineurin, and a C-terminal TxxP motif [].Calcineurin is a calcium-responsive enzyme that dephosphorylates the nuclear factor of activated T cells (NFAT). In doing so, it promotes its nuclear translocation and uniquely links calcium signalling to transcriptional regulation [].
Members of this family are found in the parasite Babesia bigemina. Other rhoptry-associated proteins are found in Plasmodium falciparum but these do not belong to this family. Animal infection with B. bigemina may produce a pattern similar to human malaria []. Rhoptry organelles form part of the apical complex in apicomplexan parasites. Rhoptry-associated proteins are antigenic, and generate partially protective immune responses in infected mammals. Thus RAPs are among the targeted vaccine antigens for babesial (and malarial) parasites. However, RAP-1 proteins are encoded by by a multigene family; thus RAP-1 proteins are polymorphic, with B and T cell epitopes that are conserved among strains, but not across species [, , ]. Antibodies to B. bigemina RAP-1 may also be helpful in the serological detection of B. bigemina infections [].
Phospholipase C gamma (PLCg), also known as 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma, is a member of the family of phosphoinositide specific PLCs that convert phosphatidylinositol 4,5-bisphosphate into second messengers 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), thereby initiating and propagating numerous cellular signaling events [].There are two forms of phospholipase C-gamma, PLCg1 and PLCg2. PLCg1 is widely distributed but the expression of PLCg2 is primarily limited to cells of haematopoietic lineage []. PLCg1 is critical in many cells, and in haematopoietic systems it is required for T cell and NK cell function, whereas PLCg2 is important in mast cells, NK cells, B cells, and platelets.PLC-gamma-1 may have a role in actin reorganisation and cell migration [].
This entry represents type IV secretion system proteins VirB3, TrbD and AvhB. Type IV secretion systems are found in plant and animal pathogens, as well as in symbiotic bacteria. The tumour-inducing (Ti) plasmid of Rhizobium radiobacter (Agrobacterium tumefaciens) encodes two DNA transfer systems: VirB and Trb, where the virB operon is required for the transfer DNA to the plant host, and the trb system is required for the conjugal transfer of the Ti plasmid between cells of Agrobacterium [, ]. In addition, VirB3 is found associated with bacterial inner and outer membranes and assists T pilus formation as an assembly factor []. The conjugal transfer protein TrbD contains a nucleotide binding motif and may provide energy for the export of DNA or the export of other Trb proteins []. This entry also includes avhB (Agrobacterium virulence homologue virB), which is most similar to the VirB type IV secretion system of Bartonella henselae (Rochalimaea henselae) [].
This entry represents the Guided entry of tail-anchored proteins factor CAMLG (also known as Calcium signal-modulating cyclophilin ligand CAML) which is required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum [, , ]. Together with GET1/WRB, acts as a membrane receptor for soluble GET3/TRC40, which recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol [, , ]. It is required for the stability of GET1 []. CAMLG also stimulates calcium signaling in T cells through its involvement in elevation of intracellular calcium [], and it is essential for the survival of peripheral follicular B cells. Although CAML shows no sequence similarity to yeast Get2, they share similar biochemical properties and topology [], thus resulting in the Get2 homologue in mammals, playing the same essential role in the membrane insertion as that of Get2. It also shows similarity with ER membrane protein complex subunit 6 (EMC6) [].
This entry represents the N-terminal domain of FlgT, a flagellar protein that make up part of the basal body of the flagellum. The flagellum is a large macromolecular assembly composed of three major parts: the basal body, the hook, and the filament. The basal body has two unique ring structures, the T ring and the H ring. FlgT is required to form and stabilise both ring structures. FlgT is composed of three domains, the N-terminal domain (FlgT-N), the middle domain (FlgT-M), and the C-terminal domain (FlgT-C). This N-terminal domain contributes to the construction of the H-ring structure, and adopts a two-layer α-β sandwich architecture composed of a four-stranded anti-parallel β-sheet and two alpha helices [].
This entry represents the C-terminal domain of a family of flagellar (FlgT) proteins that make up part of the basal body of the flagellum. FlgT is composed of three domains, the N-terminal domain (FlgT-N), the middle domain (FlgT-M), and the C-terminal domain (FlgT-C). The flagellum is a large macromolecular assembly composed of three major parts: the basal body, the hook, and the filament. The basal body has two unique ring structures, the T ring and the H ring. FlgT is required to form and stabilise both ring structures. FlgT-C is made up of seven β-strands and a helical segment, arranged in a core β-barrel structure and a β-hairpin. The C-terminal domain of FlgT is not essential but stabilises the H-ring structure [].
This domain defines serine peptidases belonging to MEROPS peptidase family S9 (clan SC), subfamily S9B (dipeptidyl-peptidase IV). The protein fold of the peptidase domain for members of this family resembles that of serine carboxypeptidase D, the type example of clan SC. This domain is an alignment of the region to the N-terminal side of the active site, which is found in .Dipeptidyl-peptidase IV () is also called adenosine deaminase-binding protein (ADA-binding protein) or CD26. The exopeptidase cleaves off N-terminal X-Pro or X-Ala dipeptides from polypeptides (dipeptidyl peptidase IV activity). It serves as the costimulatory molecule in T cell activation and is an associated marker of autoimmune diseases, adenosine deaminase-deficiency and HIV pathogenesis [, , ].
The release factor eRF1 terminates protein biosynthesis by recognising stop codons at the A site of the ribosome and stimulating peptidyl-tRNA bond hydrolysis at the peptidyl transferase centre. The crystal structure of human eRF1 is known []. The overall shape and dimensions of eRF1 resemble a tRNA molecule with domains 1, 2, and 3 of eRF1 corresponding to the anticodon loop, aminoacyl acceptor stem, and T stem of a tRNA molecule, respectively. The position of the essential GGQ motif at an exposed tip of domain 2 suggests that the Gln residue coordinates a water molecule to mediate the hydrolytic activity at the peptidyl transferase centre. A conserved groove on domain 1 is proposed to form the codon recognition site [].This entry represents the first domain of eRF1.
Interleukin-10 (IL-10) is a protein that inhibits the synthesis of a number of cytokines, including IFN-gamma, IL-2, IL-3, TNF and GM-CSF produced by activated macrophages and by helper T cells. Structurally, IL-10 is a protein of about 160 amino acids that contains four conserved cysteines involved in disulphide bonds []. IL-10 is highly similar to the Epstein-Barr virus (strain GD1) (HHV-4) (Human herpesvirus 4) BCRF1 protein which inhibits the synthesis of gamma-interferon and to Equid herpesvirus 2 (Equine herpesvirus 2) protein E7.It is also similar, but to a lesser degree, with human protein mda-7 [], a protein which has antiproliferative properties in human melanoma cells. Mda-7 only contains two of the four cysteines of IL-10.This entry represents the interleukin-10, interleukin-19, interleukin-20, interleukin-22, interleukin-24 and interleukin-26 family.
This is a family of glycine cleavage H-proteins, part of the glycine cleavage system (GCS) found in bacteria, archaea, and the mitochondria of eukaryotes. GCS is a multienzyme complex consisting of 4 different components (P-, H-, T- and L-proteins) which catalyzes the oxidative cleavage of glycine []. The H-protein shuttles the methylamine group of glycine from the P-protein (glycine dehydrogenase) to the T-protein (aminomethyltransferase) via a lipoyl group, attached to a completely conserved lysine residue [].This entry represents the glycine cleavage system H protein. The genome of Aquifex aeolicus contains one protein belonging to this group, and four more related proteins not included here; it seems doubtful that all of these homologues are authentic H proteins. The Chlamydial homologue of the H protein is nearly as divergent as the Aquifex outgroup, is not accompanied by P and T proteins, and is not included in this entry.
This entry includes proteasome subunit beta5t (also known as beta11; MEROPS identifier T01.016), a component of the thymoproteasome in which one of the 20S proteasome components, beta5i, is replaced by beta5t. The thymoproteasome is important for the development and repertoire formation of CD8+ T cells []. Beta5t is expressed only in cortical thymic epithelial cells, which are responsible for the positive selction of developing thymocytes []. The chymotryptic-like activity of the thymoproteasome is reduced, compared to the 20S proteasome []. The specificity of beta5t is predicted to be novel [], and the thymoproteasome increases production of peptides for presentation on the major histocompatability complex []. Beta5t may be a useful marker to distinguish type B3 thymomas from thymic carcinomas []. Expression of beta5t is markedly decreased in patients with Down's Syndrome [].
This entry represents the RNA recognition motif (RRM) of RNPS1 and its eukaryotic homologues. RNPS1 was originally characterised as a general pre-mRNA splicing activator, which activates both constitutive and alternative splicing of pre-mRNA in vitro []. It has been identified as a protein component of the splicing-dependent mRNP complex, or exon-exon junction complex (EJC), and is directly involved in mRNA surveillance [, ]. Furthermore, RNPS1 is a splicing regulator whose activator function is controlled in part by CK2 (casein kinase II) protein kinase phosphorylation []. It can also function as a squamous-cell carcinoma antigen recognized by T cells-3 (SART3)-binding protein, and is involved in the regulation of mRNA splicing []. RNPS1 contains an N-terminal serine-rich (S) domain, a central RNA recognition motif (RRM), and the C-terminal arginine/serine/proline-rich (R/S/P) domain.
Interferon beta has many known roles. IFNb has effects on the production of cytokines by T helper lymphocytes, can antagonize some of the proinflammatory effects of IFNgamma, is pro-apoptotic, inhibits the production of matrix metalloproteases, and alters the expression of adhesion molecules and chemokines [].Interferons []are proteins that produce antiviral and antiproliferative responses in cells. On the basis of their sequence interferons are classified into five groups: alpha, alpha-II (or omega), beta, delta (or trophoblast). The sequence differences may possibly cause different responses to various inducers, or result in the recognition of different target cell types []. The main conserved structural feature of interferons is a disulphide bond that, except in mouse beta interferon, occurs in all alpha, beta and omega sequences.
Chemokine CX3C is one of four chemokine subgroup designations based on the arrangement of the two N-terminal cysteines. Currently, the only member of this group identified to date is CX3C chemokine ligand 1 (CX3CL1), also known as fractalkine or neurotactin. The primary source of fractalkine is neurons, and it exhibits cell adhesion and chemoattractive properties in the central nervous system [, ]. Fractalkine differs structurally from the other subgroups in that it is attached to a membrane-spanning domain via a mucin-like stalk and can be proteolytically cleaved to a freely diffusible form []. Fractalkine combines properties of chemoattractant and adhesion molecule []. It is chemotatic for T cells, monocytes, and natural killer cells [, ].This entry represents the N-terminal chemokine domain of fractalkine [, ].
This entry represents a domain found in the tail assembly protein G from lambda-like viruses and their prophage.In bacteriophage lambda, the overlapping open reading frames G and T are expressed by a programmed translational frameshift to produce the tail assembly proteins G and GT []. Tail assembly protein GT shares it's N-terminal residues with tail assembly protein G, followed by residues of unique sequence []. An analogous frameshift is widely conserved among other dsDNA tailed phages in their corresponding 'G' and 'GT' tail genes even in the absence of detectable sequence homology []. The lambda tail assembly protein G and frameshift product GT are produced in a molar ratio of approximately 30:1[]. The correct molar ratio of these two related proteins, normally determined by the efficiency of the frameshift, is crucial for efficient assembly of functional tails []. Although tail assembly proteins G and GT are both required for assembly of functional tails, neither is present in mature tails [].
SH2 domain-containing protein 1A (SH2D1A) is an adaptor protein that appears to regulate B-cell differentiation via switching of SLAM (CD150)-mediated signalling pathways []. The SLAM receptor is expressed on activated T and B lymphocytes. SH2D1A inhibits SLAM self-association. SH2D1A acts by blocking the recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to a docking site in the SLAM cytoplasmic region []. Defects in SH2D1A are a cause of lymphoproliferative syndrome X-linked type 1 (XLP1) (OMIM:308240), which is also known as X-linked lymphoproliferative disease (XLPD) or Duncan disease []. XLP is a rare immunodeficiency characterised by extreme susceptibility to infection with Epstein-Barr virus (EBV) (HHV-4) (Human herpesvirus 4). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.This entry represents the SH2 domain of SH2D1A.
DAPP1/Bam32 is an adaptor protein that plays important roles in B cell receptor signalling, T cell receptor signalling and antibody affinity maturation in germinal centres []. It contains a putative myristoylation site at its N terminus, followed by a SH2 domain, and a pleckstrin homology (PH) domain at its C terminus. It translocates to the plasma membrane of B-lymphoma cells upon BCR (B-cell receptor) cross-linking; this translocation is PI3K (phosphoinositide 3-kinase)-dependent and PH domain-mediated []. This entry represents the SH2 domain of DAPP1/Bam32. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites [, , , , , ].
The adaptor protein 3BP2/SH3BP2 is a cytoplasmic adaptor that contributes to the regulation of immune responses []. The protein-tyrosine kinase Syk phosphorylates 3BP2 which results in the activation of Rac1 through the interaction with the SH2 domain of Vav1 and induces the binding to the SH2 domain of the upstream protein-tyrosine kinase Lyn and enhances its kinase activity []. 3BP2 has a positive regulatory role in IgE-mediated mast cell activation []. In lymphocytes, engagement of T cell or B cell receptors triggers tyrosine phosphorylation of 3BP2 []. 3BP2 is required for the proliferation of B cells and B cell receptor signaling. Mutations in the 3BP2 gene are responsible for cherubism resulting in excessive bone resorption in the jaw [].This entry represents the SH2 domain of SH3BP2.
Blk is a member of the Src non-receptor type tyrosine kinase family of proteins. Blk is involved in B-cell receptor signaling and B-cell development []. Unlike most other Src members Blk lacks cysteine residues in the SH4 domain that undergo palmitylation. Blk is required for the development of IL-17-producing gamma-delta T cells []. This entry represents the SH2 domain of Blk.The Src non-receptor type tyrosine kinase (SFK) family members have an unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail. The SH2 domain of SFKs is involved in kinase autoinhibition and T-cell receptor signaling. The binding SH2 domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the SFKs [].
This entry represents the SH2 domain of SOCS1.Cytokine signaling mediated by the JAK-STAT pathway plays essential roles in differentiation, maturation, proliferation and apoptosis of a various types of cells. Suppressor of cytokine signaling (SOCS) proteins are negative feedback regulators of the JAK-STAT signaling pathway. SOCS1 and SOCS3 are potent inhibitors of JAKs and can play pivotal roles in inflammation, as well as in the development and progression of cancers []. All SOCS share a central SH2 domain and a C-terminal SOCS box, but only SOCS1 and SOCS3 possess a kinase inhibitory region immediately upstream of the central SH2 [].SOCS1 plays a key role in the negative regulation of interferon-gamma signaling and in T cell differentiation [, , ].
Interleukins (IL) are a group of cytokines that play an important role in the immune system. They modulate inflammation and immunity by regulating growth, mobility and differentiation of lymphoid and other cells. Interleukin-17 (IL-17) is a potent proinflammatory cytokine produced by activated memory T cells []. The IL-17 family (of which there are 6 known members, termed IL-17A to IL-17F) is thought to represent a distinct signalling system that appears to have been highly conserved across vertebrate evolution []. Family members play an active role in inflammatory diseases, autoimmune diseases and cancer []. This entry represents interleukin-17 family IL-17A to IL-17F. Interleukin-17E has been renamed as interleukin-25 (IL-25). The orthologue from the nematode Caenorhabditis elegans, known as interleukin cytokine-related protein 17.1, is a neuromodulator of sensory responses, and the ligand for the receptor complex composed of ilcr-1 and ilcr-2 [].
Transcription factor activator protein (AP)-1, comprising Jun (c-Jun, JunB, and JunD) and Fos (c-Fos, FosB, Fra1, and Fra2) family members, plays a central role in regulating gene transcription in various biological processes []. Fos protein family members form stable heterodimerswith Jun proteins and thereby enhance their DNAbindingactivity []. This entry reprsents fos-related antigen 2 (Fra2), which is implicated in TGFbeta signalling. Fra2 is a positive regulator of bone and matrix formation in mice and humans []. Fra2 is a STAT5 (signal transducers and activators of transcription 5) target gene regulated by IL-2 in human CD4 T cells []. It may also play an important role in the pathogenesis of systemic sclerosis, an autoimmune disease of unknown etiology that affects the skin and a variety of internal organs including the lungs, heart, and gastrointestinal tract [].
Junctional adhesion molecule-like (JAML) contains 2 extracellular immunoglobulin-like domains, a transmembrane segment, and a cytoplasmic tail. JAML mRNA is expressed in hematopoietic tissues and is localised at the cell plasma membrane in the areas of cell-cell contacts []. It is a receptor that controls the migration and activation of the epithelial gamma-delta T cells through interaction with CXADR, a plasma membrane receptor found on adjacent epithelial and endothelial cells []. During acute inflammation, neutrophils infiltrate the intestinal mucosa. JAML can be cleaved from the neutrophil surface by zinc metalloproteases during theneutrophil transepithelial migration (TEM) []. These neutrophil-derived soluble JAML can bind to the epithelial tight junction protein coxsackie-adenovirus receptor (CAR) and decrease epithelial proliferation, inhibiting wound repair and promoting the recruitment of leukocytes [].
Catalases () are antioxidant enzymes that catalyse the conversion of hydrogen peroxide to water and molecular oxygen, serving to protect cells from its toxic effects []. Hydrogen peroxide is produced as a consequence of oxidative cellular metabolism and can be converted to the highly reactive hydroxyl radical via transition metals, this radical being able to damage a wide variety of molecules within a cell, leading to oxidative stress and cell death. Catalases act to neutralise hydrogen peroxide toxicity, and are produced by all aerobic organisms ranging from bacteria to man. Most catalases are mono-functional, haem-containing enzymes, although there are also bifunctional haem-containing peroxidase/catalases () that are closely related to plant peroxidases, and non-haem, manganese-containing catalases () that are found in bacteria [].This entry represents a small conserved region within catalase enzymes that carries the immune-responsive amphipathic octa-peptide that is recognised by T cells [].
Grass pollens are a major cause of type I allergy. Lol pI, the major rye grass (Lolium perenne) allergen, is a 240-amino acid protein []. Analysis of the amino acid sequence has revealed a determinant within the Lol pI molecule that is recognised by human leukocyte antigen class II-restricted T cells obtained from patients allergic to rye grass pollen []. Sequence analysis of a pollen-specific cDNA from maize has revealed a homologue (Zea mI) of the Lol pI gene []. The protein is ~70% similar to the reported amino acid sequence of Lol pIA. Southern analysis indicates Zea mI to be a member of a small multigene family in maize. Northern analysis indicates expression only in pollen, not in vegetative or female floral tissues. The timing of expression is developmentally regulated,occurring at a low level prior to the first pollen mitosis, and at a high level after post-meiotic division [].
This entry consists of several lipoproteins mainly from Mycobacterium species, collectively known as the LppX/LprAFG family. Proteins in this entry include:LprG () from Mycobacterium tuberculosis: an immunogenic 27kDa membrane-associated lipoprotein []. Expression of the LprG protein is essential for the growth of M. tuberculosis in immunocompetent mice []. Purification of LprG showed that it inhibits MHC-II antigen processing in primary human macrophages, providing a mechanism to avoid the host MHC-II-restricted CD4+ T cell response which is considered essential for control of M. tuberculosis infection []. LppX: a lipoprotein required for the translocation of complex lipids to the outer membrane of Mycobacterium tuberculosis. Its structure consists of a U-shaped β-half-barrel with a large hydrophobic cavity []. LprF: a membrane lipoprotein involved in the kdp signal transduction pathway, thought to be the primary response to osmotic stress [].lprA: a lipoprotein agonist of TLR2 that regulates innate immunity and APC function [].
RGS13 is a member of R4 subfamily of RGS family, a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs) []. Signaling is initiated when GPCRs bind to their ligands, triggering the replacement of GDP bound to the G-alpha subunits of heterotrimeric G proteins with GTP. RGSs inhibit signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form. This activity defines them as GTPase activating proteins (GAPs).RGS13 exhibits relatively restricted tissue expression in T and B lymphocytes, as well as mast cells (MCs). RGS13 acts together with RGS1 to regulate chemokine receptor signaling in germinal centre B lymphocytes [, ]. In MCs, it inhibits G protein-coupled receptor signaling and suppresses IgE-antigen-induced MC degranulation and anaphylaxis [].
This entry represents the C-terminal domain of a family of flagellar (FlgT) proteins that make up part of the basal body of the flagellum. FlgT is composed of three domains, the N-terminal domain (FlgT-N), the middle domain (FlgT-M), and the C-terminal domain (FlgT-C). The flagellum is a large macromolecular assembly composed of three major parts: the basal body, the hook, and the filament. The basal body has two unique ring structures, the T ring and the H ring. FlgT is required to form and stabilise both ring structures. FlgT-C is made up of seven β-strands and a helical segment, arranged in a core β-barrel structure and a β-hairpin. The C-terminal domain of FlgT is not essential but stabilises the H-ring structure [].
This entry represents the middle region of a family of flagellar proteins that make up part of the basal body of the flagellum. The flagellum is a large macromolecular assembly composed of three major parts: the basal body, the hook, and the filament. The basal body has two unique ring structures, the T ring and the H ring. FlgT is required to form and stabilise both ring structures. FlgT is composed of three domains, the N-terminal domain (FlgT-N), the middle domain (FlgT-M), and the C-terminal domain (FlgT-C). FlgT-N and FlgT-M are thoughtto be involved in the H-ring and the T-ring formation, respectively, and FlgT-M is also required for the stable association of FlgT with the basal body [].
This entry represents the N-terminal domain of FlgT, a flagellar protein that make up part of the basal body of the flagellum. The flagellum is a large macromolecular assembly composed of three major parts: the basal body, the hook, and the filament. The basal body has two unique ring structures, the T ring and the H ring. FlgT is required to form and stabilise both ring structures. FlgT is composed of three domains, the N-terminal domain (FlgT-N), the middle domain (FlgT-M), and the C-terminal domain (FlgT-C). This N-terminal domain contributes to the construction of the H-ring structure, and adopts a two-layer α-β sandwich architecture composed of a four-stranded anti-parallel β-sheet and two alpha helices [].
This entry represents the RNA recognition motif (RRM) of BRAP2, also known as BRCA1-associated protein, a novel cytoplasmic protein interacting with the two functional nuclear localisation signal (NLS) motifs of BRCA1, a nuclear protein linked to breast cancer. It also binds to the SV40 large T antigen NLS motif and the bipartite NLS motif found in mitosin []. BRAP2 may serve as a cytoplasmic retention protein and play a role in the regulation of nuclear protein transport [, ]. It has been shown to act as a negative regulator of nuclear import of viral proteins []. It contains an N-terminal RNA recognition motif (RRM), followed by a C3HC4-type ring finger domain and a UBP-type zinc finger.
Proteins containing this domain are composed of RNA exonuclease 1 (REX1 or Rex1p), REX3 (or Rex3p), and similar eukaryotic proteins. In yeast, REX1 and REX3 are required for 5S rRNA and MRP (mitochondrial RNA processing) RNA maturation, respectively []. They are DEDDh-type DnaQ-like 3'-5' exonucleases containing three conserved sequence motifs termed ExoI, ExoII and ExoIII, with a specific Hx(4)D conserved pattern at ExoIII. These motifs are clustered around the active site and contain four conserved acidic residues that serve as ligands for the two metal ions required for catalysis [].REX1 is the major exonuclease from this family responsible for pre-tRNA trail trimming and may also be involved in nuclear CCA turnover []. REX proteins function in the processing and maturation of many RNA species, similar to the function of Escherichia coli RNase T [].
The P protein is part of the glycine decarboxylase multienzyme complex (GDC), also annotated as glycine cleavage system or glycine synthase. GDC consists of four proteins P, H, L and T []. The P protein () binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor, carbon dioxide is released and the remaining methylamin moiety is then transferred to the lipoamide cofactor of the H protein. The reaction catalysed by this protein is:Glycine + lipoylprotein = S-aminomethyldihydrolipoylprotein + CO2 The subunit composition of glycine cleavage system P proteins have been classified into two types. Those from eukaryotes and some of the P proteins from prokaryotes (e.g. Escherichia coli) are in the homodimeric form. The rest of those from prokaryotes are heterotetrameric, with two different subunits which, based on sequence similarities, correspond respectively to the N and C-terminal halves of the eukaryotic subunit [].
The P protein is part of the glycine decarboxylase multienzyme complex (GDC), also annotated as glycine cleavage system or glycine synthase. GDC consists of four proteins P, H, L and T []. The P protein () binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor, carbon dioxide is released and the remaining methylamin moiety is then transferred to the lipoamide cofactor of the H protein. The reaction catalysed by this protein is:Glycine + lipoylprotein = S-aminomethyldihydrolipoylprotein + CO2 The subunit composition of glycine cleavage system P proteins have been classified into two types. Those from eukaryotes and some of the P proteins from prokaryotes (e.g. Escherichia coli) are in the homodimeric form. The rest of those from prokaryotes are heterotetrameric, with two different subunits which, based on sequence similarities, correspond respectively to the N and C-terminal halves of the eukaryotic subunit [].This entry represents the probable glycine dehydrogenase (decarboxylating) subunit 2 from prokaryotes.
The P protein is part of the glycine decarboxylase multienzyme complex (GDC), also annotated as glycine cleavage system or glycine synthase. GDC consists of four proteins P, H, L and T []. The P protein () binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor, carbon dioxide is released and the remaining methylamin moiety is then transferred to the lipoamide cofactor of the H protein. The reaction catalysed by this protein is:Glycine + lipoylprotein = S-aminomethyldihydrolipoylprotein + CO2 The subunit composition of glycine cleavage system P proteins have been classified into two types. Those from eukaryotes and some of the P proteins from prokaryotes (e.g. Escherichia coli) are in the homodimeric form. The rest of those from prokaryotes are heterotetrameric, with two different subunits which, based on sequence similarities, correspond respectively to the N and C-terminal halves of the eukaryotic subunit [].This entry represents the P protein homodimeric subfamily, which is found in eukaryotes and some prokaryotes, such as E. coli.
The anoctamin/TMEM16 family members include Ano1-10 (TMEM16A-J). They are membrane proteins involved in a variety of physiological functions, such as ion transport and ion channel regulation. TMEM16A and 16B are Ca(2+)-dependent Cl(-) channels; TMEM16C, 16D, 16F, 16G, and 16J have been classified as Ca(2+)-dependent lipid scramblases []. The anoctamin/TMEM16 family might have diverged in two or three different subclasses, channels, scramblases and dual-function channel/scramblases [].Anoctamin-6 (Ano6, TMEM16F) has calcium-dependent phospholipid scramblase activity []. Ano6 is a Ca(2+)-activated Cl(-) required for lipid scrambling in platelets during blood coagulation []and has an important role in chemokine-induced dendritic cell migration []. It is an essential component of the immune defense by macrophages []. Ano6 is a component of the outwardly rectifying chloride channel (ORCC) in airway epithelial cells and Jurkat T lymphocytes []. The Na(+)/Ca(2+) exchanger NCX1 requires Ano6 to efficiently translocate Ca(2+) out of osteoblasts into the calcifying bone matrix [].
This entry represents the PR/SET domain found in PR domain zinc finger protein 1 (PRDM1, also known as BLIMP-1). PRDM1 is a transcriptional repressor that is essential for cellular development. It is essential for the differentiation of B and T cells []. In Caenorhabditis elegans, it regulates the spatiotemporal cell migration pattern []. The degradation of PRDM1 by DRE-1/FBXO11-dependent mechanism regulates the C. elegans developmental timing and maturation [].The PRDM family members are characterised by the presence of a N-terminal PR (PRDI-BF1 and RIZ1 homology) domain followed by multiple zinc fingers which confer DNA binding activity. PR domains are only distantly related to the classical SET methyltransferase domains []. They are involved in epigenetic regulation of gene expression through their intrinsic histone methyltransferase activity or via interactions with other chromatin modifying enzymes [].
Receptor-binding cancer-associated surface antigen (RCAS1) and Estrogen receptor-binding fragment-associated gene 9 (EBAG9) proteins are identical. EBAG9/RCAS1 induces apoptosis and suppresses the growth of several cells such as activated T cells []. Defects in EBAG9 may be a cause of breast cancers and adenocarcinomas of the lung as it is present and overexpressed in many patients and the expression correlates with tumor grade, suggesting that it may be involved in cancer immune escape. It may not be a directly tumor-associated antigen, but rather contributes indirectly to the antigenicity of tumor cells. The selectivesuppression phenomenon of the cytotoxic immune response may be brought about by an increase in sRCAS1 blood serum concentration. Such an increase has been observed during cancer progression. RCAS1 blood serum concentration could be useful in the identification of endometriosis []and prostatic cancer [].
This entry represents glia maturation factor beta and gamma (GMFB/GMFG), Aim7 from budding yeasts and Gmf1 from fission yeasts. GMF family proteins do not interact with actin, but instead bind to Arp2/3 complex. They sever actin-Arp2/3 complex branch junctions by a cofilin-like mechanism [, ]. Human GMFB was initially identified as a growth and differentiation factor acting on neurons as well as glia in the vertebrate brain. GMFB is produced predominantly in the thymus, and may have roles in both intracellular signal transduction and T cell development [].Fission yeast Gmf1 is an actin depolymerising factor involved in the control of the disassembly of actin patches []. Aim7 binds Arp2/3 complex to stimulate filament debranching and inhibit actin nucleation [].
This domain is found in the release factor eRF1 which terminatesprotein biosynthesis by recognizing stop codons at the A site of the ribosome and stimulatingpeptidyl-tRNA bond hydrolysis at the peptidyl transferase centre. The crystal structure of human eRF1 is known []. The overallshape and dimensions of eRF1 resemble a tRNA molecule with domains 1, 2, and 3 of eRF1 corresponding to the anticodon loop,aminoacyl acceptor stem, and T stem of a tRNA molecule, respectively. The position of the essential GGQ motif at an exposed tipof domain 2 suggests that the Gln residue coordinates a water molecule to mediate the hydrolytic activity at the peptidyltransferase centre. A conserved groove on domain 1, 80 A from the GGQ motif, is proposed to form the codon recognition site [].This domain is also found in other proteins which may also be involved in translation termination
This domain is found in the release factor eRF1 which terminates protein biosynthesis by recognizing stop codons at the A site of the ribosome and stimulatingpeptidyl-tRNA bond hydrolysis at the peptidyl transferase centre. The crystal structure of human eRF1 is known []. The overallshape and dimensions of eRF1 resemble a tRNA molecule with domains 1, 2, and 3 of eRF1 corresponding to the anticodon loop,aminoacyl acceptor stem, and T stem of a tRNA molecule, respectively. The position of the essential GGQ motif at an exposed tipof domain 2 suggests that the Gln residue coordinates a water molecule to mediate the hydrolytic activity at the peptidyltransferase centre. A conserved groove on domain 1, 80 A from the GGQ motif, is proposed to form the codon recognition site [].This domain is also found in other proteins which may also be involved in translation termination but this awaits experimental verification.
This domain is found in the release factor eRF1 which terminates protein biosynthesis by recognizing stop codons at the A site of the ribosome and stimulatingpeptidyl-tRNA bond hydrolysis at the peptidyl transferase centre. The crystal structure of human eRF1 is known []. The overallshape and dimensions of eRF1 resemble a tRNA molecule with domains 1, 2, and 3 of eRF1 corresponding to the anticodon loop,aminoacyl acceptor stem, and T stem of a tRNA molecule, respectively. The position of the essential GGQ motif at an exposed tipof domain 2 suggests that the Gln residue coordinates a water molecule to mediate the hydrolytic activity at the peptidyltransferase centre. A conserved groove on domain 1, 80 A from the GGQ motif, is proposed to form the codon recognition site [].This domain is also found in other proteins for which the precise molecular function is unknown. Many of them are fromArchaebacteria. These proteins may also be involved in translation termination but this awaits experimental verification.
SH2 domain-containing protein 1A (SH2D1A) is an adaptor protein that appears to regulate B-cell differentiation via switching of SLAM (CD150)-mediated signalling pathways []. The SLAM receptor is expressed on activated T and B lymphocytes. SH2D1A inhibits SLAM self-association. SH2D1A acts by blocking the recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to a docking site in the SLAM cytoplasmic region []. Defects in SH2D1A are a cause of lymphoproliferative syndrome X-linked type 1 (XLP1) (OMIM:308240), which is also known as X-linked lymphoproliferative disease (XLPD) or Duncan disease []. XLP is a rare immunodeficiency characterised by extreme susceptibility to infection with Epstein-Barr virus (EBV) (HHV-4) (Human herpesvirus 4). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.
This domain entry includes the N terminus of the actin-interacting protein sperm-specific antigen 2 (SSFA2), also known as Ki-ras-induced actin-interacting protein (KRAP) []. In this region are found the residues that interact with inositol 1,4,5-trisphosphate receptor (IP3R, also known as ITPR). SSFA2 was first localised as a membrane-bound form with extracellular regions suggesting it might be involved in the regulation of filamentous actin and signals from the outside of the cells []. It has now been shown to be critical for the proper subcellular localisation and function of IP3R. Inositol 1,4,5-trisphosphate receptor functions as the Ca2+ release channel on specialised endoplasmic reticulum membranes, so the subcellular localisation of IP3R is crucial for its proper function [].This entry also recognises a domain in Tespa1 and in uncharacterized coiled-coil protein CCDC129. Tespa1 (thymocyte-expressed positive selection-associated protein 1) is required for the development and maturation of T-cells []. Tespa1 shows sequence homology to SSFA2 and physically associates with IP3R in T and B lymphocytes [].
This entry includes two subfamilies of the TRAFAC (translation factor related) class AIG1/Toc34/Toc159-like paraseptin GTPase family.The GTPases of immunity-associated protein (GIMAP)/immune-associated nucleotide-binding protein (IAN) subfamily is conserved among vertebrates and angiosperm plants and has been postulated to regulate apoptosis, particularly in context with diseases such as cancer, diabetes, and infections. The function of GIMAP/IAN GTPases has been linked to self defense in plants and to the development of T cells in vertebrates [, ].Plant-specific Toc (translocon at the outer envelope membrane of chloroplasts) proteins. Toc proteins function as integral components of the chloroplast protein import machinery. The Toc translocon contains the two membrane-bound GTPases Toc33/34 and Toc 159, which expose their G domains to the cytosol that recognise and then deliver precursor proteins through the translocation pore Toc75 [, ].
Proteins containing this domain include mammalian Nit1 and Nit2, the Nit1-like domain of the invertebrate NitFhit, yeast Nit3 and various uncharacterized bacterial and archaeal Nit-like proteins. In general, they are amidases involved in various metabolic processes. Nit1 is a deaminated glutathione amidase [], while Nit2 is an omega-amidase []. They are candidate tumour suppressor proteins []. In NitFhit, the Nit1-like domain is encoded as a fusion protein with the non-homologous tumour suppressor, fragile histidine triad (Fhit) []. Mammalian Nit1 and Fhit may affect distinct signal pathways, and both may participate in DNA damage-induced apoptosis []. Nit1 is a negative regulator in T cells []. Overexpression of Nit2 in HeLa cells leads to a suppression of cell growth through cell cycle arrest in G2 [].
TRIM68 is an E3 ubiquitin-protein ligase that negatively regulates Toll-like receptor (TLR)- and RIG-I-like receptor (RLR)-driven type I interferon production by degrading TRK fused gene (TFG), a novel driver of IFN-beta downstream of anti-viral detection systems []. It also functions as a cofactor for androgen receptor-mediated transcription through regulating ligand-dependent transcription of androgen receptor in prostate cancer cells []. Moreover, TRIM68 is a cellular target of autoantibody responses in Sjogren"s syndrome (SS), as well as systemic lupus erythematosus (SLE). It is also an auto-antigen for T cells in SS and SLE [, ]. TRIM68 belongs the C-IV subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, a B-box, and two coiled coil domains, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain. This entry represents the C3HC4-type RING-HC finger found in TRIM68.
The family of type 2 integral membrane protein (ITM2) consists of three members, ITM2A, ITM2B and ITM2C []. Members of this family contain a BRICHOS domain, which possesses chaperone activity [,].ITM2A is a target gene of GATA-3, a T cell-specific transcription factor [].ITM2B is proteolytically cleaved at three locations; cleavage by furin in the C-terminal region generates a 23-residue peptide (ABri23), processing by ADAM10 results in release of the BRICHOS domain from the membrane-bound N-terminal part and intramembrane cleavage by SPPL2a/2b liberates the intracellular domain []. ITM2B (BRI2) is a target of BCL6 transcriptional repression and a short form of the ITM2B protein, similarly to other targets of BCL6, induces apoptosis in hematopoietic cell lines []. ITM2B interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production [, ]. ITM2C (BRI3) also inhibits amyloid precursor protein processing, but through a different mechanism to ITM2B [].
Semaphorin-7A (Sema7A) plays regulatory roles in both immune and nervous systems. Unlike other semaphorins, which act as repulsive guidance cues, Sema7A enhances central and peripheral axon growth and is required for proper axon tract formation during embryonic development []. Sema7A also plays a critical role in the negative regulation of T cell activation and function []. Sema7A is a membrane-anchored member of the semaphorin family of proteins. Semaphorins are regulatory molecules in the development of the nervous system and in axonal guidance. They also play important roles in other biological processes, such as angiogenesis, immune regulation, respiration systems and cancer. The Sema domain is located at the N terminus and contains four disulfide bonds formed by eight conserved cysteine residues. It serves as a receptor-recognition and -binding module [].
This OB-fold domain folds into a five-stranded β-barrel []. Proteins containing this domain are found in various staphylococcal toxins described as staphylococcal superantigen-like (SSL) proteins that are related to the staphylococcal enterotoxins (SEs) or superantigens. These SSL proteins of which 11 have so far been characterised have a typical SE tertiary structure consisting of a distinct oligonucleotide/oligosaccharide binding (OB-fold), this domain, linked to a β-grasp domain, family Stap_Strp_tox_C (). SSLs do not bind to T-cell receptors or major histocompatibility complex class II molecules and do not stimulate T cells. SSLs target components of innate immunity, such as complement, Fc receptors, and myeloid cells [, , , , , , ]. SSL protein 7 (SSL7) is the best characterised of the SSLs and binds complement factor C5 and IgA with high affinity and inhibits the end stage of complement activation and IgA binding to FcgammaR [].
Glycoproteins B7-1 (CD80) and B7-2 (CD86) are expressed on antigen-presenting cells and deliver the co-stimulatory signal through CD28 and CTLA-4 (CD152) on T cells. Signalling through CD28 augments the T-cell response, whereas CTLA-4 signalling attenuates it []. CD80 contains two Ig-like domains, an amino-terminal immunoglobulin variable (IgV)-like domain characteristic of adhesion molecules and a membrane proximal immunoglobulin constant (IgC)-like domain similar to the constant domains of antigen receptors []. Members of the Ig family are components of immunoglobulin, T-cell receptors, CD1 cell surface glycoproteins, secretory glycoproteins A/C, and Major Histocompatibility Complex (MHC) class I/II molecules. In immunoglobulins, each chain is composed of one variable domain (IgV) and one or more IgC domains. These names reflect the fact that the variability in sequences is higher in the variable domain than in the constant domain. The IgV domain is responsible for antigen binding, and the IgC domain is involved in oligomerization and molecular interactions [, ].
CD38, the HUGO gene name, is also called T10 or ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase (). CD38 is a novel enzyme capable of catalysing multiple reactions, including NAD glycohydrolase, ADP-ribosyl cyclase, cyclic ADP ribose hydrolase and base-exchange activities. Two of the enzymatic products, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), are calcium messengers in a wide variety of cells from protist, plant, and mammal to human. CD38 is a positive and negative regulator of cell activation and proliferation, depending on the cellular environment. It is involved in adhesion between human lymphocytes and endothelial cells and is involved in the metabolism of two calcium messengers, cADPR and NAADP.CD157 (also called BP-3/IF-7, BST-1 or Mo5) has ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase activities. CD157 supports the growth of a pre-B cell line, DW34. Anti-CD157 mAb IF-7 has synergistic effects on anti-CD3-induced growth of T progenitor cells, and facilitates the development of [alpha][beta]TCR+ cells in foetal thymic organ culture system.
Nkap is a highly conserved protein which functions as a transcriptional repressor on Notch target genes. It is required for T cell development and acquisition of functional competency [, , , ], in transcriptional repression and maintenance and survival of adult hematopoietic stem cells [], it also plays a role in RNA splicing and processing [, ]. MSA2, the Nkap human orthologue in Arabidopsis thaliana, is involved in rRNA synthesis []. Nkap is a key regulator of mitosis, and its dysregulation might contribute to tumorigenesis by causing chromosomal instability []. Nkap promotes the proliferation, migration and invasion of Ewing sarcoma cells, through the AKT signalling pathway [].NKAP is divided into approximately three domains, N-terminal RS repeats, a highly basic middle domain and the C-terminal DUF 926 [, ].
This entry represents a group of lipid metabolizing enzymes, including LACT and LPLA2 from humans, and PDAT from plants.Lecithin:cholesterol acyltransferase (LACT), also known as phosphatidylcholine-sterol acyltransferase (), is involved in extracellular metabolism of plasma lipoproteins, including cholesterol. It esterifies the free cholesterol transported in plasma lipoproteins, and is activated by apolipoprotein A-I. Its structure has been revealed []. Defects in LACT cause Fish eye disease and familial LCAT deficiency [].Phospholipid:diacylglycerol acyltransferase (PDAT)() is involved in triacylglycerol formation by an acyl-CoA independent pathway. The enzyme specifically transfers acyl groups from the sn-2 position of a phospholipid to diacylglycerol, thus forming an sn-1-lysophospholipid [].Lysosomal phospholipase A2 (LPLA2) () plays important roles for lung surfactant metabolism and maturation of invariant natural killer T cells. Its structure has been revealed [].
Cbl-b, also known as RNF56, has been identified as a regulator of antigen-specific, T cell-intrinsic, peripheral immune tolerance, a state also known as clonal anergy. It may inhibit activation of the p85 subunit of phosphoinositide 3-kinase (PI3K), protein kinase C-theta (PKC-theta) []and negatively regulates T-cell receptor-induced transcription factor nuclear factor kappaB (NF-kappaB) activation []. In addition, Cbl-b may target multiple signaling molecules involved in transforming growth factor (TGF)-beta-mediated transactivation pathways []. Cbl-b contains a tyrosine-kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, is composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain), a proline rich domain, a nuclear localization signal, a C3HC4-type RING-HC finger and an ubiquitin-associated (UBA) domain []. This entry represents the C3HC4-type RING-HC finger.
This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C terminus of butyrophilin family 3A (BTN3A). Duplication events have led to three paralogues in primates: BTN3A1, BTN3A2, and BTN3A3. BTNs belong to receptor glycoproteins of immunoglobulin (Ig) superfamily, characterised by the presence of extracellular Ig-like domains (IgV and/or IgC). BTN3 transcripts are ubiquitously present in all immune cells (T cells, B cells, NK cells, monocytes, dendritic cells, and hematopoietic precursors) with different expression levels; BTN3A1 and BTN3A2 are expressed mainly by CD4+ and CD8+ T cells, BTN3A2 is the major form expressed in NK cells, and BTN3A3 is poorly expressed in these immune cells [, ].The PRY/SPRY domain of the BTN3A1 isoform mediates phosphoantigen (pAg)-induced activation by binding directly to the pAg [, , ].
Beta-2-microglobulin (Beta2m) constitutes the 12kDa light chain of the class I major histocompatibility complex (MHC-I) on the surface of many cells, to which it is non-covalently associated. It is also found in the serum in a free form. Beta-2-microglobulin co-association with the MHC class I heavy chain is prerequisite for functional expression of the protein complex on the cell surface. Together these function in the presentation of nine amino acid peptides to the T-cell receptor of CD8-bearing T lymphocytes and killer inhibitory receptors on natural killer cells.Beta2m contains a β-sandwich domain composed of two facing β-sheets (four stranded and three stranded), that is typical of the C-type immunoglobulin superfamily. This structure is stabilized by an intramolecular disulfide bridge connecting two Cys residues in the facing beta -sheets [].
