Ribonuclease T () is an enzyme found so far only in gamma-subdivision proteobacteria such as Escherichia coli and Xylella fastidiosa. Ribonuclease T is homologous to the DNA polymerase III alpha chain. It can liberate AMP from the common C-C-A terminus of uncharged tRNA. It appears also to be involved in RNA maturation. It also acts as a 3' to 5' single-strand DNA-specific exonuclease; it is distinctive for its ability to remove residues near a double-stranded stem. Ribonuclease T is a high copy suppressor in E. coli of a UV-repair defect caused by deletion of three other single-stranded DNA exonucleases [].
The troponin (Tn) complex regulates calcium-induced muscle contraction. Tn contains three subunits, Ca2+ binding (TnC), inhibitory (TnI), and tropomyosin binding (TnT), which is required for Ca(2+)-mediated activation of actomyosin ATPase activity [, ]. Three different troponin T genes that encode tissue-specific isoforms of subunit T have been found in mammals and birds, encoding cardiac (TNNT2), slow (TNNT1), and fast (TNNT3) skeletal muscle TnT isoforms [, , , ].Mutations of the TNNT1gene cause nemaline myopathy [], while mutations of the TNNT2 gene cause familial hypertrophic cardiomyopathy [, ], and mutations of the TNNT3 gene cause Arthrogryposis, distal, 2B2 (DA2B2) [].
This entry represents selenoprotein T (SelT), which is conserved from plants to humans. SelT is localized to the endoplasmic reticulum through a hydrophobic domain. The protein binds to UDP-glucose:glycoprotein glucosyltransferase (UGTR), the endoplasmic reticulum (ER)-resident protein, which is known to be involved in the quality control of protein folding [, ]. Selenium (Se) plays an essential role in cell survival and most of the effects of Se are probably mediated by selenoproteins, including selenoprotein T. The function of SelT is unknown, although it may have a role in PACAP signaling during PC12 cell differentiation [, ].
This entry includes the peptidase M14-like domain of carboxypeptidase (CP) T (CPT; MEROPS identifier M14.007). CPT belongs to the M14 family of metallocarboxypeptidases (MCPs) []. The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity []. CPT has moderate similarity to CPA and CPB, and exhibits dual-substrate specificity by cleaving C-terminal hydrophobic amino acid residues like CPA and C-terminal positively charged residues like CPB []. The substrate specificity difference between CPT and CPA and CPB is ascribed to a few amino acid substitutions at the substrate-binding pocket while the spatial organization of the binding site remains the same as in all Zn-CPs []. CPT has increased thermal stability in presence of Ca2+ions, and two disulfide bridges which give an additional stabilization factor.
Antigen (Ag) recognition by the T cell receptor (TCR) induces activation ofT lymphocytes. However, TCR-mediated signals alone are insufficient forefficient T cell activation, and additional co-stimulatory signals are required. One of the most important surface molecules that delivers co-stimulatory signals for T cells is CD28. The human T lymphocyte Ag CD28 (Tp44) is a homodimeric 90kDa glycoprotein expressed on the surface of themajority of human peripheral T cells and lymphocytes. Stimulation of CD4+ Tcells in the absence of CD28 co-signalling causes impaired proliferation, reduced cytokine production and altered generation of helper T cell subsets.Co-stimulation via CD28 promotes T cell viability, clonal expansion,cytokine production and effector functions, while also regulating apoptosisof activated T cells, suggesting its importance in regulating long-term T cell survival [, , , ].Ligands for CD28 and the structurally related CTLA-4 (CD152) are themolecules B7.1 (CD80) and B7.2 (CD86). B7.1 and B7.2 are expressed onprofessional antigen presenting cells (APCs) and their expression is up-regulated during an immune response. Ligation of CD28 by its natural ligandsresults in tyrosine phosphorylation at a YMNM motif within its cytoplasmictail. The phosphorylated motif subsequently interacts with the Src homology2 domain in the p85 regulatory subunit of P13K, activating the p110 catalytic subunit. One of the P13K-dependent downstream targets, resulting from the antibody cross-linking of CD28, is the phoshporylation and activation of Akt (or PKB). Constitutively active Akt is able to substitutefor CD28 signals, and stimulates IL-2 production when introduced into matureCD28-deficient cells. Another molecule affected by CD28 stimulation is theproto-oncogene Vav, which acts as a guanine-nucleotide exchange factor forRac and CDC42, allowing these molecules to switch from the inactive GDP-bound state to the active GTP-bound state [, ].Another interesting feature of CD28, is its ability to induce expression ofPDE7, a cAMP phosphodiesterase, thus reducing cellular cAMP levels. cAMP hasbeen reported to affect nearly every pathway important for lymphocyteactivation, leading to inhibition of T cell proliferation. Specifically,increased intracellular cAMP has been implicated in the induction of T cellanergy, a non-responsive state that occurs after T cells are stimulatedthrough TCR/CD3 in the absence of co-stimulation. This can have therapeutic implications, in that blockage of CD28 co-stimulation can be profoundlyimmunosuppressive, preventing induction of pathogenic T cell responses inautoimmune disease models, and allowing for prolonged acceptance of allografts in models of organ transplantation []. Finally, CD28 co-stimulation directly controls T cell cycle progression by down-regulating the cdk inhibitor p27kip1, which actually integratesmitogenic MEK and P13K-dependent signals from both TCR and CD28 [].
Arabidopsis protein FLOWERING LOCUS T (FT) is a floral integrator protein that can be induced by CONSTANS (CO) protein, a light regulated transcriptional activator []. It acts partially redundant with its paralogue, TWIN SISTER OF FT (TSF), to induce flowering [, ]. It may play a role in both the autonomous and the long-day flowering pathways []. This entry also includes FT homologues from rice, known as Hd3a and Hd3b, which are also involved in flower development [].
This entry represents the centromere protein T (CENP-T). CENP-T is a component of the CENPA-NAC (nucleosome-associated) complex, which plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation [, ]. CENP-T and CENP-W form a complex that is directly involved in establishment of centromere chromatin structure coordinately with CENP-A []. Histone-fold-containing CENP-T-W and CENP-S-X complexes can form a stable CENP-T-W-S-X heterotetramer. Structural analysis of the CENP-T-W-S-X complex suggests that it can form a unique nucleosome-like structure to generate contacts with DNA []. The CENP-T homologue in S. pombe is also known as Cnp20 [].
The group of polyomaviruses is formed by the homonymous murine virus (Py) as well as other representative members such as the simian virus 40 (SV40) and the human BK and JC viruses []. Their large T antigen (T-ag) protein binds to and activates DNA replication from the origin of DNA replication (ori). Insofar as is known, the T-ag binds to the origin first as a monomer to its pentanucleotide recognition element. The monomers are then thought to assemble into hexamers and double hexamers, which constitute the form that is active in initiation of DNA replication. When bound to the ori, T-ag double hexamers encircle DNA []. T-ag is a multidomain protein that contains an N-terminal J domain, which mediates protein interactions (see , ), a central origin-binding domain (OBD), and a C-terminal superfamily 3 helicase domain (see , ) [].This group represents a large T antigen, Polyomaviridae type.The oncogenic large tumour antigen (LTag) is a protein found in polyomaviruses which is essential for viral DNA replication []. LTag contains three domains, an N-terminal DnaJ domain which mediates protein interactions (), a domain which binds the origin of DNA replication (), and a C-terminal helicase domain. Replication is intitated by LTag assembling at the origin as a double hexamer that distorts and melts the origin DNA [, ]. During elongation LTag acts as a helicase that unwinds duplex DNA at the replication forks [].
This entry represents the 'T' domain of 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 [].
The group of polyomaviruses is formed by the homonymous murine virus (Py) as well as other representative members such as the simian virus 40 (SV40) and the human BK and JC viruses []. Their large T antigen (T-ag) protein binds to and activates DNA replication from the origin of DNA replication (ori). Insofar as is known, the T-ag binds to the originfirst as a monomer to its pentanucleotide recognition element. The monomers are then thought to assemble into hexamers and double hexamers, which constitute the form that is active in initiation of DNA replication. When bound to the ori, T-ag double hexamers encircle DNA []. T-ag is a multidomain protein that contains an N-terminal J domain, which mediates protein interactions (see , ), a central origin-binding domain (OBD), and a C-terminal superfamily 3 helicase domain (see , ) [].This entry represents the central origin-binding domain (OBD). The overall fold of the ~130-residue T-ag OBD can be described as a central five-stranded antiparallel β-sheet flanked by two α-helices on one side and one α-helix and one 3(10)-helix on the other. Both faces of the central β-sheet are largely hydrophobic and are protected from solvent by the helices, thus forming two hydrophobic cores []. The T-ag OBD molecules are arranged as a spiral with a left-handed twist having six T-ag OBD's per turn. The spiral surrounds a central channel, the inner wall of which consists of alpha helices [].
Members of this protein family are stage V sporulation protein T (SpoVT), a protein of the sporulation/germination program in Bacillus subtilis and related species. The amino-terminal 50 amino acids are nearly perfectly conserved across all endospore-forming bacteria. SpoVT is a DNA-binding transcriptional regulator related to AbrB [].
The glycine cleavage system (GCS) is a multienzyme system composed of proteins P, H, T, and L, that catalyses the reversible oxidation of glycine. The T protein is an aminomethyl transferase that catalyses the following reaction:(6S)-tetrahydrofolate + S-aminomethyldihydrolipoylprotein = (6R)-5,10-methylenetetrahydrofolate + NH3+ dihydrolipoylproteinThe glycine cleavage system is found in bacteria and the mitochondriaof eukaryotes. Mutations in the human T-protein gene are known to cause nonketotic hyperglycinemia [].
The group of polyomaviruses is formed by the homonymous murine virus (Py) as well as other representative members such as the simian virus 40 (SV40) and the human BK and JC viruses []. Their large T antigen (T-ag) protein binds to and activates DNA replication from the origin of DNA replication (ori). Insofar as is known, the T-ag binds to the origin first as a monomer to its pentanucleotide recognition element. The monomers are then thought to assemble into hexamers and double hexamers, which constitute the form that is active in initiation of DNA replication. When bound to the ori, T-ag double hexamers encircle DNA []. T-ag is a multidomain protein that contains an N-terminal J domain, which mediates protein interactions (see , ), a central origin-binding domain (OBD), and a C-terminal superfamily 3 helicase domain (see , ) [].This entry represents the helicase domain of LTag, which assembles into a hexameric structure containing a positively charged central channel that can bind both single- and double-stranded DNA []. ATP binding and hydrolysis trigger large conformational changes which are thought to be coupled to the melting of origin DNA and the unwinding of duplex DNA []. These conformational changes cause the angles and orientations between regions of a monomer to alter, creating what was described as an "iris"-like motion in the hexamer. In addition to this, six beta hairpins on the channel surface move longitudinally along the central channel, possibly serving as a motor for pulling DNA into the LTag double hexamer for unwinding.
This domain is the C-terminal domain of the CD4 T cell receptor. The C-terminal domain is the cytoplasmic domain which relays the signal for T cell activation. This process involves co-receptor internalisation. This domain is involved in binding to the N-terminal of Lck co-receptor in a Zn2+ clasp structure.
The glycine cleavage system (GCS) is a multienzyme system composed of proteins P, H, T, and L, that catalyses the reversible oxidation of glycine. The T protein is an aminomethyl transferase that catalyses the following reaction:(6S)-tetrahydrofolate + S-aminomethyldihydrolipoylprotein = (6R)-5,10-methylenetetrahydrofolate + NH3+ dihydrolipoylproteinThe glycine cleavage system is found in bacteria and the mitochondriaof eukaryotes. This entry representsthe T-protein from bacteria [].
Antigenic stimulation of T lymphocytes initiates a complex series ofintracellular signal transduction pathways that leads to the expression of apanel of immunoregulatory genes, whose function is critical to theinitiation and coordination of the immune response. The multi-subunitnuclear factor of activated T cells (NFAT) transcription factor familyplays a pivotal role in this process and is involved in the expression of anumber of immunologically important genes. These include the cytokines IL-2,IL-3, IL-4, IL-5, granulocyte-macrophage colony-stimulating factor, andtumour necrosis factor-alpha, as well as several cell-surface molecules,such as CD40L and FasL. Although originally described in T cells, it is nowapparent that NFAT proteins are also expressed in other immune system cells,including B cells, mast cells, basophils and natural killer cells, as wellas in a variety of non-immune cell types and tissues, such as skeletalmuscle, neurons, heart and adipocytes. However, although NFAT acts as acalcium-dependent transcription factor and serves to couple gene expressionto changes in intracellular calcium levels in most cases, NFAT target geneshave not been identified in these latter cell types.NFAT proteins appear to be regulated primarily at the level of theirsubcellular localisation []. They are found exclusively in the cytoplasm ofresting T cells, and consist of 2 components: a pre-existing cytoplasmiccomponent that translocates into the nucleus on calcium mobilisation, and aninducible nuclear component comprising members of the activating protein-1(AP-1) family of transcription factors. In response to antigen receptorsignalling, the calcium-regulated phosphatase calcineurin acts directly todephosphorylate NFAT proteins, causing their rapid translocation from thecytoplasm to the nucleus, where they cooperatively bind their target
A key event in the regulation of the adaptive immune response is the bindingof major histocompatibility complex (MHC)-peptide complexes to T cellantigen receptors (TCRs). The formation of such ternary complexes inducessignificant biochemical changes within T cells of the host animal. The firstdetectable response of the T cell is the rapid accumulation of numeroustyrosine-phosphorylated proteins within the cell. Increased phosphotyrosineoccurs as a consequence of the activation of several different TCR-associated, hematopoietic-specific protein kinases (PTKs), thereby perturbingthe balance between those enzymes that add, and those that remove,phosphates from key tyrosine residues. These initial phosphorylation eventsare required for the subsequent activation of the small guanosinetriphosphatase (GTPase) proteins Ras and Rac, the lipid kinase P13K and PLC-gamma1. Activation of these cytoplasmic signalling proteins ultimately leadsto activation of various transcription factors (NF-AT, NF-kB, and AP-1) andincreased transcription from genes that have an important role in initiatingT cell proliferation, such as interleukin-2 (IL-2) [].An unresolved question in the field has been which molecules and whatsequence of events tie together the early tyrosine phosphorylation eventswith the activation of these downstream signalling molecules. A likelycandidate for linking the proximal and distal portions of the TCR signallingpathway is a 36kDa transmembrane protein termed LAT. LAT becomesphosphorylated after TCR engagement, thereby creating binding sites for theSrc homology 2 (SH2) domains of other proteins, including PLC-gamma1, Grb2,Gads, Grap, 3BP2 and Shb. It also indirectly binds SOS, c-Cbl, Vav, SLP-76and Itk.LAT is expressed in peripheral blood lymphocytes, thymus and spleen, aswell as in other blood cells, including megakaryocytes, platelets, naturalkiller cells and mast cells. It is excluded from the cytosol, and is foundat the plasma membrane and in the perinuclear compartment. The cellularlocalisation of LAT seems to be extremely sensitive to alternations in theintracellular redox balance. Reduced intracellular levels of antioxidantsresult in the membrane displacement of LAT (a consequence of aconformational change interfering with its insertion into the membrane),abrogation of TCR-mediated signalling and, consequently, hyporesponsivenessof T lymphocytes.The amino acid sequence of LAT contains no recognised functional domains,but, consistent with its strong tyrosine phosphorylation upon TCRstimulation, its predicted cytoplasmic tail contains 10 tyrosines, 9 ofwhich are conserved between mouse, rat and human proteins. In addition,LAT also has 2 cysteine residues (Cys26 and Cys29 in human) that areconserved among human, rat, mouse and bovine proteins. These residues lieproximal to the inner face of the plasma membrane: Cys26 within the TMregion andCys29 located juxtamembrane. These membrane-proximal residuesare thought to play a vital role in LAT function. In fact, LAT is subject topost-translational palmitoylation of these residues, which appears to benecessary to target LAT to lipid rafts in the membrane, where it canrecruit key cytosolic signalling proteins to the aggregated rafts upon TCRstimulation. Raft membrane domains are envisaged as lateral assemblies ofsphingolipids and cholesterol that form ordered membrane phases [].
This is a family of 15kDa salivary proteins from Acari Arachnids that is induced on feeding and assists the parasite to remain attached to its arthropod host. By repressing calcium fluxes triggered by TCR engagement, Salp15 inhibits CD4+ T cell activation and interleukin (IL)-2 production [, ]. Salp15 shows weak similarity to Inhibin A, a member of the TGF-beta superfamily that inhibits the production of cytokines and the proliferation of T cells.
This family consists of CbiQ and NikQ. CbiQ is part of the ECF transporter complex CbiMNOQ involved in cobalt import []. It can also transport nickel with a very low affinity [, ]. NikQ is part of ECF transporter complex NikMNQO involved in nickel import. Similarly, it can also transport cobalt, but with a very low affinity [].
Chemoreception is mediated in Caenorhabditis elegans by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs) of proteins which are of the serpentine type []. Srt is a member of the Srg superfamily of chemoreceptors. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf' [].
Leukosialin (CD43, sialophorin) is a large sialoglycoprotein expressed widely in various leukocytes (granulocytes, monocytes/macrophages and T-lymphocytes) []. It is involved in leukocyte adhesion and migration [, ]. Leukosialin interacts with the T cell receptor (TcR) to initiate signaling events during T cell priming []. The CD43 signaling pathway induces the expression of IFN-gamma by effector CD4+ T cells (Th, helper T cells) and to a lesser extent CD8+ T cells (Tc, cytotoxic T cells) []. Besides its role in progression of the T cell differentiation program, CD43 plays a role in T cell homing from lymphoid organs to peripheral tissues [, , ].
Amb V is an Ambrosia sp (ragweed) pollen allergen. Amb t V has been shown to contain a C-terminal helix as the major T cell epitope. Free sulphydryl groups also play a major role in the T cell recognition of cross-reactivity T cell epitopes within these related allergens [].
LAX is a family of proteins is found in chordates. LAX is membrane-associated and expressed in B cells, T cells, and other lymphoid-specific cell types. It down-regulates antigen-receptor signalling in T cells by inhibiting TCR-mediated p38 MAPK activation [, ].
Amb V is an Ambrosia sp (ragweed) pollen allergen. Amb t V has been shown to contain a C-terminal helix as the major T cell epitope. Free sulphydryl groups also play a major role in the T cell recognition of cross-reactivity T cell epitopes within these related allergens [].Structurally, Amb V has an alpha+beta fold composed of three antiparallel strands followed by a short alpha helix.
FYN-binding protein 1 (FYB1), also known as ADAP or SLAP, is an adapter protein in beta 1 integrin signalling and T lymphocyte migration []. It has been found to co-localise with F-actin in membrane ruffles, adhesion plaques/podosomes and phagocytic cups [, ]. In activated T cells, Fyb/SLAP associates with Ena/VASP family proteins and may link T cell signalling to the actin cytoskeleton remodelling []. FYB1 also interacts with mammalian actin binding protein 1 (mAbp1) that affects F-actin dynamics [].
TNFSF18, also known as GITRL (glucocorticoid-induced TNF receptor ligand), binds to its receptor GITR on both effector and regulatory T cells and generates positive costimulatory signals []. GITR is also activated by a GITR ligand called SECTM1A []. The costimulatory effect of GITR activation in T cells has been shown to increase T cell expansion and cytokine production, exacerbate autoimmune/inflammatory diseases, favour tumour rejection, perform viral and parasite clearance, and potentiate immune/inflammatory responses [, ].
The function of C6orf120 protein is not clear. C6orf120 recombinant protein has been shown to induce apoptosis of Jurkat cells and primary CD4(+) T cells [].
The CD2 adhesion molecule is a cell surface protein expressed by T cells and natural killer cells. CD2's extracellular domain contains immunoglobulin-like domains that are glycosylated at two sites and can mediate homodimerisation []. Ligation of CD2 by CD58 in humans or CD48 in mice helps T cells adhere to antigen-presenting cells, and initiates signal transduction pathways that enhance signalling through the T cell receptor for antigen. CD2 knockout mice exhibit essentially normal immune function [], and it is thought that CD2 is somewhat functionally redundant with other T cell co-stimulatory receptors such as CD28 [].
The LFA-3 (CD2) adhesion molecule is a cell surface protein expressed by T cells and natural killer cells. LFA-3's extracellular region contains immunoglobulin-like domains that are glycosylated at two sites and can mediate homodimerisation []. Ligation of LFA3 by CD58 in humans or CD48 in mice helps T cells adhere to antigen-presenting cells, and initiates signal transduction pathways that enhance signalling through the T cell receptor for antigen. LFA-3 knockout mice exhibit essentially normal immune function [], and it is thought that LFA-3 is somewhat functionally redundant with other T cell co-stimulatory receptors such as CD28 [].
T-cell activation inhibitor, also known as tolerance associated gene-1, is a mitochondrial protein that may have a role in regulation of T cell activation or apoptosis [, ].
This domain is found in eukaryotic proteins, including T-cell activation inhibitor, which may have a role in regulation of T cell activation or apoptosis [, ].
SIT (or Sit1) is a transmembrane adapter protein that negatively regulates signalling from the T-cell receptor (TCR) [, , ]. SIT regulates T cell development and peripheral homeostasis.
The troponin (Tn) complex regulates Ca2+induced muscle contraction. Tn contains three subunits, Ca2+binding (TnC), inhibitory (TnI), and tropomyosin binding (TnT). This entry includes domains from troponin T and troponin I. Troponin I binds to actin and troponin T binds to tropomyosin [, , ]. Structurally this domain forms a heterodimeric coiled coil.
This entry contains mite allergens Der p 5 []and Blo t 5 [], belonging to the mite group 5 allergen family, Blo t 21 []and Der f 21 belonging to group 21. Mite allergens causes an allergic reaction in humans []. Common symptoms of mite allergy are bronchial asthma, allergic rhinitis and conjunctivitis. Der p 5 binds to IgE.
Members of this family of Yersinia pseudotuberculosis mitogens adopt a sandwich structure consisting of nine strands in two beta sheets, in a jelly-roll topology. As with other superantigens, they are able to excessively activate T cells by binding to the T cell receptor [].
This entry contains mite allergens Der p 5 []and Blo t 5 [], belonging to the mite group 5 allergen family, Blo t 21 []and Der f 21 belonging to group 21. Mite allergens causes an allergic reaction in humans []. Common symptoms of mite allergy are bronchial asthma, allergic rhinitis and conjunctivitis. Der p 5 binds to IgE.
This entry includes a variety of exonuclease proteins, such as ribonuclease T []and the epsilon subunit of DNA polymerase III. Ribonuclease T is responsible for the end-turnover of tRNA,and removes the terminal AMP residue from uncharged tRNA. DNA polymerase III is a complex, multichain enzyme responsible for most of the replicative synthesis in bacteria, and also exhibits 3' to 5' exonuclease activity.
CD70 is a ligand of CD27 and is a TNF related transmembrane protein induced upon activation on T and B cells []. The CD27/CD70 interaction plays a key role in T dependent B cell responses and is responsible for plasma cell differentiation []. The CD27/CD70 pathway has been shown to contribute to the pathophysiology of autoimmunity [].
Members of this family of Yersinia pseudotuberculosis mitogens adopt a sandwich structure consisting of nine strands in two beta sheets, in a jelly-roll topology. As with other superantigens, they are able to excessively activate T cells by binding to the T cell receptor [].
T cell-dependent immune processes require cell-surface interactions thatmediate the initiation, modulation and the ultimate course of the response.The specificity of T cell recognition is determined by the engagement of theT cell receptor (TCR) on T cells with cognate peptide-MHC complexes presented by antigen presenting cells (APCs). Additional signals arerequired to sustain and enhance T cell activity, the most important of whichis provided by the engagement of CD28 on T cells with its ligands B7-1(CD80) and B7-2 (CD86). By contrast, the interaction of B7 isoformswith cytotoxic T lymphocyte-associated molecule-4 CTLA-4, a CD28 homologue receptor on T cells (31% identity), provides inhibitory signals requiredfor down-regulation of the response, while it may also prevent T cell activation by weak TCR signals[, , , , ].Sequence comparison between human CTLA-4 and CD28 proteins suggests they arehomologous, with the highest of degree of similarity being in the juxta-membrane and cytoplasmic regions. In addition, the cytoplasmic domainsof human and murine CTLA-4 are identical, suggesting that this region hasimportant functional properties [].
The troponin (Tn) complex regulates Ca2+induced muscle contraction. Tn contains three subunits, Ca2+binding (TnC), inhibitory (TnI), and tropomyosin binding (TnT). This family includes troponin T and troponin I. Troponin I binds to actin and troponin T binds to tropomyosin [, , ].
This domain can be found in transposase IS66 from Agrobacterium tumefaciens []. Transposases are necessary for efficient DNA transposition. IS66 may cause genetic and structural variations of the T region and the vir region of the octopine Ti plasmids [].
This entry represents a group of animal antimicrobial proteins, such as granulysin from humans and NK-lysinfrom horses [, ]. Granulysin is produced by human cytolytic T lymphocytes and natural killer cells that kills Mycobacterium tuberculosis [].
This group of metallopeptidases belong to MEROPS peptidase family M29 (aminopeptidase T family, clan M-). The protein fold of the peptidase domain and the active site residues are not known for any members of the thermophilic metallo-aminopeptidases family [].
Transmembrane protein PVRIG, also known as CD112 receptor (CD112R), is the cell surface receptor for NECTIN2 (CD antigen CD112). CD112R functions as a coinhibitory receptor for T cells, competing with CD226 to bind to CD112 [].
Lysis inhibition (LIN) accessory protein rIII is thought to inhibit cell lysis by binding to the cytoplasmic part of holin T, stabilizing the holin-antiholin complex and preventing lysis by blocking the hole-forming function of the T holin [].
Roquin-1 (RC3H1) is a post-transcriptional repressor required to repress follicular helper T cells (Tfh) and autoimmunity []. It binds to messenger RNAs (mRNAs) and regulates gene expression posttranscriptionally. For instance, it controls ICOS (inducible costimulator) expression through binding to the 3' UTR of ICOS mRNA and by interacting with proteins that confer post-transcriptional repression []. Besides ICOS, it also represses Ox40 and interferon-gamma in T cells, and this helps to prevent inappropriate T cell activation and Tfh cell differentiation [, ].Roquin-1 and its paralogue, Roquin-2 (Rc3h2), have been found to redundantly repress the mRNAs controlling T follicular helper cells and systemic inflammation [, ]. Tfhs are helper T-cells specialised in facilitating B-cell responses [].
F-box only protein 38 (FBX38) is an E3 ubiquitin ligase that mediates Lys48-linked poly-ubiquitination and subsequent proteasome degradation of PD-1, an immune checkpoint mediator and negative regulator of T cell-mediated immunity [].
Adenoviruses have evolved multiple mechanisms to evade the host immune response. Several of the immunomodulatory adenoviralproteins are encoded in early transcription unit 3 (E3). The E3A/19K protein interferes with antigen presentation and T cell recognition [].
This entry represents a conserved site, which includes includes the motif KGCYxGQE, that is found in glycine cleavage system T proteins (GcvT) and in the bacterial tRNA-modifying protein YgfZ.
Members of the OTUD5 (OTU domain-containing protein 5) family are deubiquitinases. Human OTUD5, also known as DUBA, functions as negative regulator of the innate immune system [, ]and is a post-translational suppressor of IL-17 production in T cells [].
T cell-dependent immune processes require cell-surface interactions thatmediate the initiation, modulation and the ultimate course of the response.The specificity of T cell recognition is determined by the engagement of theT cell receptor (TCR) on T cells with cognate peptide-MHC complexes presented by antigen presenting cells (APCs). Additional signals arerequired to sustain and enhance T cell activity, the most important of whichis provided by the engagement of CD28 on T cells with its ligands B7-1(CD80) and B7-2 (CD86). By contrast, the interaction of B7 isoformswith cytotoxic T lymphocyte-associated molecule-4 CTLA-4, a CD28 homologue receptor on T cells (31% identity), provides inhibitory signals requiredfor down-regulation of the response, while it may also prevent T cell activation by weak TCR signals[, , , , ].Unlike CD28, which is not expressed on resting T cells, CTLA-4 is not detected on the cell surface until 24 hours after activation. In fact, Tcell activation leads to both increased CTLA4 gene expression andtrafficking of CTLA4 protein to the cell surface. In addition, CTLA-4exhibits an affinity for the B7 isoforms that is 10 to 100 times that forCD28. Covalent dimerisation of CTLA4 is required for its high bindingavidity, but each monomeric subunit also contains a binding site for CD80and CD86. It is likely that CTLA-4 directly competes with CD28 for bindingB7 and also directs the assembly of inhibitory signalling complexes thatlead to quiescence or anergy. Thus the balance between the opposing signals elicited by CD28 and CTLA-4 is central to the regulation of T cellresponsiveness and homeostasis. One mechanism by which CTLA-4 may performthis function is by regulating cell-cycle progression; by contrast with CD28, which down-regulates the cell-cycle inhibitor p27kip1, CTLA-4 prevents this degradation[, , ].Sequence comparison between human CTLA-4 and CD28 proteins suggests they arehomologous, with the highest of degree of similarity being in the juxta-membrane and cytoplasmic regions. In addition, the cytoplasmic domainsof human and murine CTLA-4 are identical, suggesting that this region hasimportant functional properties [].Typically, activation of T cells by TCR-engaging peptide-MHC is dramatically enhanced by interaction of the CD28 co-stimulatory receptor with its ligands CD80 (B7-1) and CD86 (B7-2) on the APC surface. Interestingly, CTLA-4 is transported from intracellular stores toward the region of the cell surface receiving activation signals. This suggests that binding of CD28 to its ligand may occur primarily at the centre of the mature immunological synapse, and that CTLA-4 may be transported to this site under certain circumstancesto block or reverse this effect.
VirB proteins are suggested to act at the bacterial surface and there play an important role in directing t-DNA transfer to plant cells. VirB6 from Agrobacterium tumefaciens is an essential component of the type IV secretion machinery for T pilus formation and genetic transformation of plants. Absence of VirB6 leads to reduced cellular levels of VirB5 and VirB3, which were proposed to assist T pilus formation as minor component(s) or assembly factor(s), respectively [, ].
This entry is found in several mammalian signalling lymphocytic activation molecule (SLAM) proteins. Optimal T cell activation and expansion require engagement of the TCR plus co-stimulatory signals delivered through accessory molecules. SLAM, a 70kDa co-stimulatory molecule belonging to the Ig superfamily, is defined as a human cell surface molecule that mediates CD28-independent proliferation of human T cells and IFN-gamma production by human Th1 and Th2 clones []. SLAM has also been recognised as a receptor for Measles virus [].
Programmed cell death protein 1 (PDCD1), also known as PD1, is an immune-checkpoint receptor mainly expressed by T cells that negatively regulates immune response []. It interacts with its ligands PD-L1 and PD-L2 to inhibit T cell effector functions in an antigen-specific manner []. The PD1-mediated inhibitory pathway is exploited by some tumours to attenuate anti-tumour immunity and escape destruction by the immune system [].
The H protein (GcvH) of the glycine cleavage system shuttles the methylamine group of glycine from the P protein to the T protein. Most Chlamydia lack the P and T proteins, and have a single homologue of GcvH that appears deeply split from canonical GcvH in molecular phylogenetic trees. The proteins in this entry areonly found in the Chlamydiae, and always are part of a two-gene operon, upstream of the homologue of GcvH. Its function is unknown.
This entry includes FYN-binding protein 1 and 2 (FYB1, FYB2) and PML-RARA-regulated adapter molecule 1 (PRAM1). Most of the proteins in this entry contain an altered SH3 domain fold.FYN-binding protein 1 (FYB1), also known as ADAP or SLAP, is an adapter protein in beta 1 integrin signalling and T lymphocyte migration []. It has been found to co-localise with F-actin in membrane ruffles, adhesion plaques/podosomes and phagocytic cups [, ]. In activated T cells, Fyb/SLAP associates with Ena/VASP family proteins and may link T cell signalling to the actin cytoskeleton remodelling []. FYB1 also interacts with mammalian actin binding protein 1 (mAbp1) that affects F-actin dynamics [].FYN-binding protein 2 (FYB2, also known as ARAP) is a adaptor protein required for TCR signaling and integrin-mediated adhesion [].PRAM1 is an intracellular adaptor molecule that is upregulated during the induced granulocytic differentiation of promyelocytic leukemic cells and during normal human myelopoiesis [].
FYN-binding protein 1 (FYB1), also known as ADAP or SLAP, is an adapter protein in beta 1 integrin signalling and T lymphocyte migration []. It has been found to co-localise with F-actin in membrane ruffles, adhesion plaques/podosomes and phagocytic cups [, ]. In activated T cells, Fyb/SLAP associates with Ena/VASP family proteins and may link T cell signalling to the actin cytoskeleton remodelling []. FYB1 also interacts with mammalian actin binding protein 1 (mAbp1) that affects F-actin dynamics [].The SH3 domain of FYB adopts an altered fold referred to as a helically extended SH3 (hSH3) domain characterised by clusters of positive charges. The hSH3 domain can no longer bind conventional proline-rich peptides; instead, it functions as a novel lipid interaction domain and can bind acidic lipids such as phosphatidylserine, phosphatidylinositol, phosphatidic acid, and polyphosphoinositides [, , ].
This domain is found in Interleukin-7 receptor subunit alpha (IL-7Ralpha), which together IL-7 form a complex crucial to several signalling cascades leading to the development and homeostasis of T and B cells. IL-7Ralpha carries a 219 residue ectodomain on the N-terminal region which is crucial for T and B-cell development. Mutations in the IL-7Ralpha ectodomain inhibits T and B cell development, resulting in patients with a form of severe combined immunodeficiency (SCID). The ectodomain folds into two fibronectin type III (FNIII) domains connected by a 310-helical linker. This entry comprises the first of the two FNIII domains, D1. In the D1 domain of IL-7Ralpha, a disulfide bond (C22R-C37R) conserved among cytokine receptor class I (CRH I) family members bridges two beta strands [].
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.Class II MHC glycoproteins are expressed on the surface of antigen-presenting cells (APC), including macrophages, dendritic cells and B cells. MHC II proteins present peptide antigens that originate extracellularly from foreign bodies such as bacteria. Proteins from the pathogen are degraded into peptide fragments within the APC, which sequesters these fragments into the endosome so they can bind to MHC class II proteins, before being transported to the cell surface. MHC class II receptors display antigens for recognition by helper T cells (stimulate development of B cell clones) and inflammatory T cells (cause the release of lymphokines that attract other cells to site of infection) [].MHC class II molecules are comprised of two membrane-spanning chains, alpha and beta, of similar size. Both chains consist of two globular domains (N- and C-terminal), and a transmembrane segment to anchor them to the membrane []. A groove in the structure acts as the peptide-binding site.This superfamily represents the N-terminal domain of both the alpha and beta chains, which share the same α-helical/β-sheet fold, where the α-helical and β-sheet regions are segregated.
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.Class II MHC glycoproteins are expressed on the surface of antigen-presenting cells (APC), including macrophages, dendritic cells and B cells. MHC II proteins present peptide antigens that originate extracellularly from foreign bodies such as bacteria. Proteins from the pathogen are degraded into peptide fragments within the APC, which sequesters these fragments into the endosome so they can bind to MHC class II proteins, before being transported to the cell surface. MHC class II receptors display antigens for recognition by helper T cells (stimulate development of B cell clones) and inflammatory T cells (cause the release of lymphokines that attract other cells to site of infection) [].MHC class II molecules are comprised of two membrane-spanning chains, alpha and beta, of similar size. Both chains consist of two globular domains (N- and C-terminal), and a transmembrane segment to anchor them to the membrane []. A groove in the structure acts as the peptide-binding site.This entry represents the N-terminal domain (also called beta-1 domain) of the beta chain.
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.Class II MHC glycoproteins are expressed on the surface of antigen-presenting cells (APC), including macrophages, dendritic cells and B cells. MHC II proteins present peptide antigens that originate extracellularly from foreign bodies such as bacteria. Proteins from the pathogen are degraded into peptide fragments within the APC, which sequesters these fragments into the endosome so they can bind to MHC class II proteins, before being transported to the cell surface. MHC class II receptors display antigens for recognition by helper T cells (stimulate development of B cell clones) and inflammatory T cells (cause the release of lymphokines that attract other cells to site of infection) [].MHC class II molecules are comprised of two membrane-spanning chains, alpha and beta, of similar size. Both chains consist of two globular domains (N- and C-terminal), and a transmembrane segment to anchor them to the membrane []. A groove in the structure acts as the peptide-binding site.This entry represents the N-terminal domain (also called alpha-1 domain) of the alpha chain.
Nuclear factor interleukin-3-regulated protein (NFIL3, also known as E4BP4) was first identified as a transcriptional repressor capable of binding an activating transcription factor (ATF) DNA consensus sequence site in the adenovirus E4 promoter []. Later, it was independently identified as a transactivator of the IL3 promoter in human T cells [].E4BP4 is involved in a several biological processes, including transcriptional control of the circadian clock, neuron growth and survival, osteoblast function, and regulation of ovulation []. It is essential for the development of NK cells and CD8alpha(+) conventional dendritic cells, and is also involved in macrophage activation, polarisation of CD4(+) T cell responses and B cell class switching to IgE [].
Synaptotagmin-3 (SYT3) belongs to the synaptotagmin family, which is a group of membrane-trafficking proteins that contain two C-terminal C2 domains. Most of the synaptotagmins have a unique N-terminal domain that is involved in membrane anchoring or specific ligand binding. SYT3 is required for the formation and delivery of cargo to the perinuclear endocytic recycling compartment (ERC) []. Among synaptotagmins 1-11, SYT3 is the only one that is expressed in T cells. It is essential for chemokine receptor CXCR4 recycling in T cells and thereby affects CXCL12 chemokine-induced migration [].
The H protein (GcvH) of the glycine cleavage system shuttles the methylamine group of glycine from the P protein to the T protein. Most Chlamydia lack the P and T proteins, and have a single homologue of GcvH that appears deeply split from canonical GcvH in molecular phylogenetic trees. This protein family represents the Chlamydial GcvH homologue, which is always seen as part of a two-gene operon, downstream of a member of the uncharacterised protein family . The function of the proteins in this entry are unknown.
Two related oncogenes, TCL-1 and MTCP-1 , are overexpressed in T cell prolymphocytic leukemias as a result of chromosomal rearrangements that involve the translocation of one T cell receptor gene to either chromosome 14q32 or Xq28 [].TCL-1 is an all-beta protein consisting of an eight-stranded antiparallel beta barrel with a novel topology. The barrel consists of two four-stranded β-meander motifs, related by a two fold axis and connected by a long loop. The structure of MTCP-1 is very similar, diverging only in regions that are either flexible and/or involved in crystal packing [, ].
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-15 (IL-15) has a variety of biological functions, including stimulation and maintenance of cellular immune responses []. It is required for division of CD8+ T cells of memory phenotype, a process that is increased by inhibition of IL-2 []. The numbers of CD8+ memory T cells in animals may, therefore, be controlled by a balance between IL-15 and -2. This entry represents interleukin-15.
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. This entry represents Interleukin-22 (IL-22), that belongs to the family of IL-10-related cytokines, which includes IL-10, -19, -20, -22, -24 and -26 []. It is produced by activated T cells and acts as a T cell mediator, promoting the innate, non-specific immunity of tissues []. IL-22 also regulates early defence mechanisms against attaching and effacing (A/E) bacterial pathogens []. This entry represents interleukin-22.
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-15 (IL-15) has a variety of biological functions, including stimulation and maintenance of cellular immune responses []. It is required for division of CD8+ T cells of memory phenotype, a process that is increased by inhibition of IL-2 []. The numbers of CD8+ memory T cells in animals may, therefore, be controlled by a balance between IL-15 and -2. This entry represents the interleukin-15 and interleukin-21 family.
SYR-related high mobility group (HMG) box (SOX) family proteins are a conserved group of transcriptional regulators defined by the presence of a highly conserved HMG box domain that mediates DNA binding []. SOX-12, together with SOX-4 and SOX-11, belongs to the subgroup C of the SOX gene family, with SOX-4 and SOX-11 being function redundantly with SOX-12 [, ]. SOX-12 plays a critical role in embryonic development and cell-fate determination during organogenesis [, ]. It has been shown to promote hepatocellular carcinoma invasion and metastasis []. Sox-12 is involved in the development of peripheral T regulatory cells under inflammatory conditions and sufficient to promote Foxp3 expression in CD4+ T cells [].
The CD8 alpha subunit is a component of the CD8 α-β heterodimer and is additionally found as a homodimeric complex []. Both of these species assist in the recognition of MHC class I-peptide complexes by the α-β T cell receptor (TCR). CD8 binds to constant regions of the peptide-MHC complex and augments antigen-specific interactions that are formed by the TCR []. Additionally, CD8 is directly coupled to TCR signalling by virtue of its interactions with the p56Lck kinase [], aswell as other proteins. CD8 expression is limited to and one of the defining characteristics of cytolytic T cells.
The troponin (Tn) complex regulates calcium-induced muscle contraction. Tn contains three subunits, Ca2 binding (TnC), inhibitory (TnI), and tropomyosin binding (TnT), which is required for Ca(2)-mediated activation of actomyosin ATPase activity [, ]. Three different troponin T genes that encode tissue-specific isoforms of subunit T have been found in mammals and birds, encoding cardiac (TNNT2), slow (TNNT1), and fast (TNNT3) skeletal muscle TnT isoforms [, , , ].This entry represents the fast (TNNT3) skeletal muscle TnT isoform. Defects in TNNT3 are a cause of distal arthrogryposis type 2B (DA2B); also known as arthrogryposis multiplex congenita, distal, type 2B (AMCD2B) [].
This superfamily represents a domain found in a group of metallopeptidases that belong to MEROPS peptidase family M29 (aminopeptidase T family, clan M-), and that includes AmpS and AmpT.Staphylococcus aureus aminopeptidase S (AmpS) has been named for its predicted, but experimentally untested, aminopeptidase activity. The enzyme is homologous to biochemically characterized aminopeptidases. It is a dimeric protein with a very unusual, elongated shape and a large internal cavity []. Aminopeptidase T (AmpT) from Thermus thermophilus is an homologue of AmpS. AmpT, like AmpS, can be divided into an N-terminal domain and a C-terminal domain, with a flexible hinge between them []. This entry represent the N-terminal domain.
This domain of unknown function has a conserved HPD sequence motif. There are two completely conserved residues (N and F) that may be functionally important. The domain is found in eukaryotic proteins, including T-cell activation inhibitor which may have a role in regulation of T cell activation or apoptosis [, ].
Synaptotagmin-like protein 3 (SYTL3, also known as Slp3) belongs to the synaptotagmin-like protein family, which contains a N-terminal RabBD (Rab-binding) domain and two C-terminal C2 domains. Slp3 binds phospholipids in the presence of calcium ions []. In mouse cytotoxic T lymphocytes, Slp3 is an effector of Rab27a and interacts with kinesin-1 through the tetratricopeptide repeat of the kinesin-1 light chain [].
Rho family-interacting cell polarization regulator 2 (also known as protein FAM65B) is a plasma membrane-associated protein of hair cell stereocilia that is essential for hearing []. It is important for formation of the HDAC6-dysferlin protein complex during myogenic cell differentiation []. It is a RhoA inhibitor involved in T lymphocyte migration and neutrophil polarization [, ].
Thymic stromal lymphopoietin (TSLP) is a cytokine that functions mainly on myeloid cells; it induces the release of T cell-attracting chemokines from monocytes and enhances the maturation of CD11c(+) dendritic cells []. TSLP has proliferative effects on the myeloid cell line []and may initiate asthma or atopic dermatitis responses by directly activating mast cells [].
The Rel homology domain (RHD) is composed of two structural domains, an N-terminal DNA-binding domain () and a C-terminal dimerisation domain. This is the dimerisation domain [].This domain can be found in both nuclear factor of activated T cells (NFAT) and nuclear factor kappa-B (NFkB), which are RHD-containing transcription factors [].
Mycoplasma arthritidis-derived mitogen (MA-Mit) adopts a completely α-helical structure consisting of ten α-helices arranged in two orthogonal bundles. MA-Mit is a superantigen that can activate large fractions of T cells bearing particular TCR V-beta elements. Two MA-Mit molecules form an asymmetric dimer and cross-link two MHC antigens to form a dimerised MA-Mit-MHC complex [].
This family consists of the B melanoma antigen (BAGE) peptides. The BAGE gene encodes a human tumour antigen that is recognised by a cytolytic T lymphocyte. BAGE genes are expressed in melanomas, bladder and lung carcinomas and in a few tumours of other histological types [].This entry also includes bacterial proteins from the Vibrionaceae family.
This family consists of the leader peptide of the histidine (his) operon. The his operon contains all the genes necessary for histidine biosynthesis. The region corresponding to the untranslated 5'-end of the transcript, named the his leader region, displays the typical features of the T box transcriptional attenuation mechanism which is involved in the regulation of many amino acid biosynthetic operons [].
Tumor necrosis factor receptor superfamily member 9 (TNFRSF9), also known as CD137, ILA or 4-1BB, plays a role in the immunobiology of human cancer where it is preferentially expressed on tumor-reactive subset of tumor-infiltrating lymphocytes. It can be expressed by activated T cells, but to a larger extent on CD8 than on CD4 T cells []. In addition, CD137 expression is found on dendritic cells, follicular dendritic cells, natural killer cells, granulocytes and cells of blood vessel walls at sites of inflammation []. It transduces signals that lead to the activation of NF-kappaB, mediated by the TRAF adaptor proteins. CD137 contributes to the clonal expansion, survival, and development of T cells []. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. CD137 is modulated by SAHA treatment in breast cancer cells, suggesting that the combination of SAHA with this receptor could be a new therapeutic approach for the treatment of tumors [].Mostly, CD137 in teleosts have not been characterized.This entry represents the N-terminal domain of TNFRSF9/CD137 from teleosts. 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 9 (TNFRSF9), also known as CD137, ILA or 4-1BB, plays a role in the immunobiology of human cancer where it is preferentially expressed on tumor-reactive subset of tumor-infiltrating lymphocytes. It can be expressed by activated T cells, but to a larger extent on CD8 than on CD4 T cells []. In addition, CD137 expression is found on dendritic cells, follicular dendritic cells, natural killer cells, granulocytes and cells of blood vessel walls at sites of inflammation []. It transduces signals that lead to the activation of NF-kappaB, mediated by the TRAF adaptor proteins. CD137 contributes to the clonal expansion, survival, and development of T cells []. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. CD137 is modulated by SAHA treatment in breast cancer cells, suggesting that the combination of SAHA with this receptor could be a new therapeutic approach for the treatment of tumors [].This entry represents the N-terminal domain of TNFRSF9. 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 [, , ].
This is the C-terminal domain found in NF-kappa-B-activating protein (Nkap) and a hypothetical open reading frame on chromosome 6, c6orf194. It is the HDAC3 binding domain required for transcriptional repression []. Nkap functions as a transcriptional repressor on Notch target genes, and is required for T cell development and acquisition of functional competency [, , ].
This entry represents a C-terminal domain found in members of the T complex protein 10 family. This domain contains unusual G repeats []. Centromere protein J, a member of the TCP10 family, inhibits microtubule nucleation from the centrosome and depolymerises taxol-stabilised microtubules []. T-complex is involved in spermatogenesis in mice [].
This family consists of several group XII secretory phospholipase A2 precursor (PLA2G12) () proteins. Group XII and group V PLA(2)s are thought to participate in helper T cell immune response through release of immediate second signals and generation of downstream eicosanoids [].
This entry represents a group of DnaJ domain-containing proteins from cyanobacteria and plants, including chloroplast NAD(P)H-quinone oxidoreductase subunit T (NdhT) from Arabidopsis. Interestingly, chloroplast NDH is more similar to cyanobacterial NDH-1, which is believed to be an origin of chloroplast NDH [].
This entry represents a domain found in some restriction endonucleases, such as MvaI and BcnI. These enzymes both function as monomers. MvaI cleaves the sequence CC/WGG, where W is an A or a T nucleotide, leaving sticky ends. BcnI cleaves the sequence CC/SGG, where S is G or C, leaving sticky ends [, ].
Thymic stromal lymphopoietin (TSLP) is a cytokine that functions mainly on myeloid cells; it induces the release of T cell-attracting chemokines from monocytes and enhances the maturation of CD11c(+) dendritic cells []. TSLP has proliferative effects on the myeloid cell line []and may initiate asthma or atopic dermatitis responses by directly activating mast cells [].
Killer cell lectin-like receptor subfamily G member 1 (KLRG1) is a co-inhibitory receptor inhibiting the activity of T and NK cells []. Its ligands include E-cadherin and N-cadherin. Binding of E-cadherin to KLRG1 has been shown to inhibits effector T-cell function [].
Roquin-2 is an E3 ubiquitin ligase required for ROS-induced ubiquitination and degradation of ASK1 (Apoptosis signal-regulating kinase 1) []. It also mediates mRNA deadenylation by recognising a conserved class of stem-loop RNA degradation motifs []. Its structure has been revealed [].Roquin-2 and its paralogue, Roquin-1 (Rc3h1), have been found to redundantly repress the mRNAs controlling T follicular helper cells and systemic inflammation [, ].
Voltage-dependent calcium channel gamma-like subunit (also known as Tmem37) has a role in stabilising the calcium channel in an inactivated (closed) state. It is a subunit of the L-type calcium channels that modulate calcium current when coexpressed with CACNA1G (calcium channel, voltage-dependent, T type, alpha 1G subunit) [].
T-cell surface protein tactile (CD96) is a membrane bound receptor of the immunoglobulin superfamily. It is expressed by both T and NK cells []. CD96 interact with CD155, and the hCD155/hCD96 axis may play a role in target cell elimination by NK cells [].
TNFSF9, also known as 4-1BBL, is a member of the tumor necrosis factor (TNF) superfamily and is the ligand for the TNFR superfamily receptor, 4-1BB. 4-1BB plays an immunomodulatory role in T cells and NK cells. Human h4-1BB has been targeted with agonists in cancer immunotherapy. The structure of 4-1BBL has be revealed [, , ].
This entry represents a family of transmembrane proteins, which function as a negative regulator of MYRF in oligodendrocyte differentiation and myelination. Interacts with the C-terminal of MYRF inhibiting MYRF self-cleavage and N-fragment nuclear translocation []. The secreted TMEM98 form promotes differentiation of T helper 1 cells (Th1) [].
Cystatin-F is a cysteine peptidase inhibitor that is targeted to endosomal/lysosomal compartments. It is synthesized as an inactive disulfide-linked dimer which is then converted to an active monomer by proteolytic cleavage of 15 N-terminal residues. It has been shown to regulate the cytotoxicity of natural killer (NK) cells and T cells [, ].
CD7 is a member of the immunoglobulin superfamily. Normal expression of CD7 is largely confined to T cells and natural killer (NK) cells. However, it is highly expressed in acute T-cell leukemia (T-ALL) and in a subset of peripheral T-cell lymphomas [].
Mycoplasma arthritidis-derived mitogen (MA-Mit) adopts a completely α-helical structure consisting of ten α-helices arranged in two orthogonal bundles. MA-Mit is a superantigen that can activate large fractions of T cells bearing particular TCR V-beta elements. Two MA-Mit molecules form an asymmetric dimer and cross-link two MHC antigens to form a dimerised MA-Mit-MHC complex [].
