CD4 is a glycoprotein found on the surface of T cells. It is a co-receptor that assists the T cell receptor (TCR) in communicating with an antigen-presenting cell (APC). The structure of a soluble fragment of CD4 has been determined to 2.3 A and reveals that the molecule has two intimately-associated immunoglobulin-like domains connected by a continuous beta strand. Residues implicated in HIV recognition reside in domain D1. Domain D2 is distinguished by a variation in the β-strand topologies of antibody domains that results in a truncated β-barrel with a non-standard intra-sheet disulphide bond [, ]. The binding sites for monoclonal antibodies, class II major histocompatibility complex molecules, and HIV gp120 can be mapped on the molecular surface. Ligation of CD4 by MHC-II on blood monocytes mediates macrophage differentiation and it also increases the susceptibility of blood-derived monocytes to HIV binding and subsequent infection [].
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 envelope glycoprotein Gp160 of HIV1 is cleaved into the surface protein Gp120 and the transmembrane protein Gp41. The entry of HIV requires interaction of viral Gp120 with the CD4 glycoprotein and a chemokine receptor on the cell surface [].
The human immunodeficiency virus type 1 Vpu transmembrane protein is required for the induction of degradation human CD4 receptor degradation in the endoplasmic reticulum, and for the enhancement of virus particle release from the plasma membrane of infected cells. The cytoplasmic domain of Vpu directly interacts with the CD4 receptor, targeting it for proteasome degradation []. The cytoplasmic domain encompasses the C-terminal half of the 81-residue protein, and is comprised of a few helical turns without an apparent hydrophobic core [].
The human immunodeficiency virus type 1 Vpu transmembrane protein is required for the induction of degradation human CD4 receptor degradation in the endoplasmic reticulum, and for the enhancement of virus particle release from the plasma membrane of infected cells. The cytoplasmic domain of Vpu directly interacts with the CD4 receptor, targeting it for proteasome degradation []. The cytoplasmic domain encompasses the C-terminal half of the 81-residue protein, and is comprised of a few helical turns without an apparent hydrophobic core []. The transmembrane domain of Vpu, found towards the N terminus, forms a cation-selective ion channel and is responsible for the enhancement of virus particle release [].
Prolactin-inducible (PIP) is a 17kDa glycoprotein that binds to many proteins including fibrinogen, actin, keratin, myosin, immunoglobulin G, CD4, and human zinc-alpha-2 glycoprotein []. It forms a complex with human serum albumin (HSA) in seminal plasma and may affect male fertility/infertility []. It also acts as a factor capable of suppressing T-cell apoptosis through itsinteraction with CD4 [].
This domain adopts an immunoglobulin-like β-sandwich with seven strands in 2 beta sheets, in a Greek key topology. It is predominantly found in the extracellular portion of CD4 proteins, where it enables interaction with major histocompatibility complex class II antigens [].
Apelin is a bioactive peptide with a wide variety of physiological actions, which are mediated by its interaction with its specific G protein-coupled receptor, APJ []. The protein is cleaved into several different active forms, including apelin-36, apelin-17 and apelin-13. Apelin has been shown to be involved in the regulation of cardiovascular and fluid homeostasis, food intake, cell proliferation, and angiogenesis []. It has also been shown to inhibit human immunodeficiency virus type 1 entry into cells coexpressing CD4 and APJ [].
CD160 is a GPI-anchored MHC-class I activating receptor mainly expressed on peripheral blood NK cells. It is also expressed on both cytolytic lymphocytes and some unstimulated CD4 T cells []. CD160 has different isoforms, including GPI-anchored isoform, a transmembrane isoform, and a secreted isoform. Upon specific engagement of CD160 by its physiological ligand HLA-C, or by mAb cross-linking, CD160 PB-NK cells produce significant levels of IFN-gamma, TNF-alpha, IL-6 as well as IL-8 and MIP-1beta [].
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 []. This entry represents C2-set domains, which are Ig-like domains resembling the antibody constant domain. C2-set domains are found primarily in the mammalian T-cell surface antigens CD2 (Cluster of Differentiation 2), CD4 and CD80, as well as in vascular (VCAM) and intercellular (ICAM) cell adhesion molecules.CD2 mediates T-cell adhesion via its ectodomain, and signal transduction utilising its 117-amino acid cytoplasmic tail []. CD2 displays structural and functional similarities with African swine fever virus (ASFV) LMW8-DR, a protein that is involved in cell-cell adhesion and immune response modulation, suggesting a possible role in the pathogenesis of ASFV infection []. CD4 is the primary receptor for HIV-1. CD4 has four immunoglobulin-like domains in its extracellular region that share the same structure, but can differ in sequence. Certain extracellular domains may be involved in dimerisation [].
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 [].
This entry represents protein unc-119 homologue A (UNC119) from vertebrates, also known as retinal protein 4 (RG4) [], and the homologue from Drosophila []. It is highly expressed in retinal photoreceptor inner segments and synaptic regions. Nevertheless, UNC119 has been detected in leukocytes (eosinophils), T-cells, lung fibroblasts, the adrenal glands, cerebellum and kidney. It interacts with several diverse proteins, such as Arf-like GTPases ARL2/ARL3 [, ]and the Ca2+-binding protein CaBP4 []. It has been shown to activate Src-type tyrosine kinases associated with the interleukin-5 receptor and the T-cell receptor. It is also required for G protein trafficking in sensory neurons [].Mutations in the UNC119 gene cause immunodeficiency 13 (IMD13), a rare and heterogeneous syndrome defined by a reproducible reduction in the CD4 T-lymphocyte count [].
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 [, , ].
Lck is a member of the Src non-receptor type tyrosine kinase family of proteins. CD4 and CD8 directly couple with Lck, and cross-linking of these receptors leads to Lck activation [, ]. The N-terminal tail of Lck is myristoylated and palmitoylated and it tethers the protein to the plasma membrane of the cell. Lck also contains an SH3 domain, an SH2 domain, and a C-terminal tyrosine kinase domain. Lck has 2 phosphorylation sites, the first an autophosphorylation site that is linked to activation of the protein and the second which is phosphorylated by Csk, which inhibits it. Lck is also inhibited by SHP-1 dephosphorylation and by Cbl ubiquitin ligase, which is part of the ubiquitin-mediated pathway []. This entry represents the SH2 domain of Lck.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 [].
