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CD4 CD4 molecule [ Homo sapiens (human) ]

Gene ID: 920, updated on 6-Jul-2014
Official Symbol
CD4provided by HGNC
Official Full Name
CD4 moleculeprovided by HGNC
Primary source
HGNC:1678
See related
Ensembl:ENSG00000010610; HPRD:01740; MIM:186940; Vega:OTTHUMG00000168514
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
CD4mut
Summary
This gene encodes a membrane glycoprotein of T lymphocytes that interacts with major histocompatibility complex class II antigenes and is also a receptor for the human immunodeficiency virus. This gene is expressed not only in T lymphocytes, but also in B cells, macrophages, and granulocytes. It is also expressed in specific regions of the brain. The protein functions to initiate or augment the early phase of T-cell activation, and may function as an important mediator of indirect neuronal damage in infectious and immune-mediated diseases of the central nervous system. Multiple alternatively spliced transcript variants encoding different isoforms have been identified in this gene. [provided by RefSeq, Aug 2010]
Location:
12p13.31
Exon count :
10
Annotation release Status Assembly Chr Location
106 current GRCh38 (GCF_000001405.26) 12 NC_000012.12 (6789472..6820810)
105 previous assembly GRCh37.p13 (GCF_000001405.25) 12 NC_000012.11 (6898638..6929976)

Chromosome 12 - NC_000012.12Genomic Context describing neighboring genes Neighboring gene parathymosin Neighboring gene lymphocyte-activation gene 3 Neighboring gene G protein-coupled receptor 162 Neighboring gene leprecan-like 2

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

Associated conditions

Description Tests
Okt4 epitope deficiency
MedGen: C3151379 OMIM: 613949 GeneReviews: Not available
not available

NHGRI GWAS Catalog

Description
Genome-wide association study identifies three common variants associated with serologic response to vitamin E supplementation in men.
NHGRI GWA Catalog

Replication interactions

Interaction Pubs
Knockdown of CD4 by siRNA inhibits HIV-1 replication in HeLa-derived TZM-bl cells PubMed
Knockdown of CD4 by siRNA inhibits HIV-1 replication in HeLa P4/R5 cells PubMed

Protein interactions

Protein Gene Interaction Pubs
Env, gp160, envelope glycoprotein env The double alanine mutations at HIV-1 Env positions 671 and 674 result in attenuation of Env-mediated cell-cell fusion and hemifusion, as well as viral infectivity mediated by both CD4-dependent and CD4-independent viruses PubMed
env CD4-linker-DC-SIGN fusion proteins enhance binding affinity to HIV-1 gp140 and gp120 in comparison to sCD4 and sDC-SIGN. These fusion proteins inhibit HIV-1 capture and transfer via DC-SIGN-expressing cells and iMDDCs PubMed
env DC-SIGN increases the binding affinity of trimeric gp140 envelope glycoproteins to CD4 on permissive cell surface PubMed
env HIV-1 Env from subtype P downregulates CD4 cell surface expression PubMed
env Binding gp140 to the synthetic CD4-mimicking mini protein leads to an outward domain shift of the three gp120 subunits, which diminishes gp120-gp41 interactions PubMed
env A soluble HIV-1 Env trimeric construct may better expose crucial epitopes such as the CD4 binding site and V3, as well as epitopes in the vicinity of gp41, subsequent to conjugation with the synthetic CD4-mimicking mini protein PubMed
env Coexpression of HIV-1 gp160 and human CD4 in HeLa cells severely impairs HIV-1 gp120 production due to the formation of intracellular gp160-CD4 complexes; this CD4-mediated inhibition of gp160 processing is alleviated by coexpression of Vpu PubMed
env Interaction of HIV-1 gp160 with CD4 increases p56lck autophosphorylation and kinase activity PubMed
env ICAM-1 promotes HIV-1 gp160-mediated syncytium formation, and the ICAM-1 contrareceptor LFA-1 attenuates the syncytium-inhibiting activity of virus-neutralizing monoclonal antibodies and soluble CD4 PubMed
env HIV-1 gp160 and gp120 specifically recognize the C-terminal heparin-binding domain of fibronectin (Fn) and this binding inhibits the interaction of gp160/gp120 with soluble CD4 PubMed
env HIV-1 gp160 molecules exist predominantly as a dimer, but higher forms corresponding to trimers and tetramers are also observed; multiple CD4 molecules bind to the gp160 oligomers PubMed
env A complete disappearance of surface CD4 preceding single-cell death occurs in cell clones expressing gp160, in which a complex between CD4 and gp160 is formed and then accumulates intracellularly PubMed
env HIV-1 glycoprotein gp160 binds to both cell surface receptor and soluble CD4 and the interaction of gp160 with CD4 results in virus-cell and cell-cell fusion PubMed
env Newly synthesized CD4 and HIV-1 gp160 form a complex prior to transport from the endoplasmic reticulum (ER) PubMed
env Dimeric HIV-1 gp160 binds to two CD4 molecules PubMed
env HIV-1 gp160 alone or CD4/gp160 cross-linking induces tyrosine phosphorylation of intracellular substrates p59fyn, zap 70, and p95vav and also leads to ras activation PubMed
env Amino acid residues 257, 368, 370, and 457 of HIV-1 gp160 are critical for both cell surface and intracellular interaction between gp160 and CD4 PubMed
env Interaction of the anchoring domain of HIV-1 gp160 with the endoplasmic reticulum membrane is responsible for gp160-mediated cell surface downregulation of CD4 PubMed
Envelope surface glycoprotein gp120 env The layer 3 residues (amino acids 247-254 and 476-483) of HIV-1 gp120 are located in the beta8 strand and alpha5 helix of the CD4-bound gp120. The five layer 3 mutants T248A, H249A, R476A, N478A, and W479A exhibit decreased CD4-binding activity PubMed
env Gelsolin overexpression impairs HIV-1 gp120-induced cortical F-actin reorganization and capping and gp120-mediated CD4-CCR5 and CD4-CXCR4 redistribution in permissive lymphocytes PubMed
env HIV-1 gp120 binds and signals through CD4, which leads to T cell activation with upregulation of the CXCR5, PD-1, Fas, and FasL expression PubMed
env CD4-mediated endocytosis of HIV-1 gp120 results in MHC-II (HLA-DR) presentation to CD4+ T cells PubMed
env Immature HIV-1 virions are competent for CD4-induced gp120 conformational changes PubMed
env HIV-1 gp120-mediated inhibition of IFN-alpha production involves CD4 and BDCA2 in plasmacytoid dendritic cells PubMed
env CD4 binding shifts the V1/V2 regions of HIV-1 gp120 to unmask the co-receptor binding site, and triggers profound dynamic changes in gp120 spanning from the binding site to the gp41-interactive face of gp120 PubMed
env Brain-derived HIV-1 Env gp120 proteins efficiently use very low levels of CD4 to enter cells, whereas lymph-node-derived gp120 proteins are dependent on higher levels of CD4 to enter cells PubMed
env N425K mutation of HIV-1 gp120 impacts CD4 interactions and confers HIV-1 resistance to maraviroc (MVC) PubMed
env Small molecule BMS-488043 inhibits the interaction of HIV-1 gp120 with CD4 by blocking the rotation of the Trp112 located on the alpha1 helix of gp120 PubMed
env CD4-linker-DC-SIGN fusion proteins enhance binding affinity to HIV-1 gp140 and gp120 in comparison to sCD4 and sDC-SIGN. These fusion proteins inhibit HIV-1 capture and transfer via DC-SIGN-expressing cells and iMDDCs PubMed
env HIV-1 induces an elongated phenotype in infected CD4+ T cells. These HIV-infected T cells tether to other lymph node CD4+ cells and form syncytia through gp120/gp41, and migrate to distant tissues to disseminate PubMed
env The N260Q gp120 mutant has a significantly lower binding to the recombinant soluble CD4 in comparison with wild-type PubMed
env Human alpha-defensin-5 binds to both HIV-1 gp120 and CD4 and blocks the interaction of CD4 with gp120, which leads to inhibit HIV-1 replication in human primary CD4+ T lymphocytes PubMed
env Feglymycin, a natural Streptomyces-derived 13mer peptide, inhibits HIV-1 gp120 binding to CD4 PubMed
env A single Y681H substitution in HIV-1 gp41 increases the gp120-CD4 binding and enhances infectivity in low CD4 expressing cells PubMed
env The net charge of HIV-1 gp120 V3 loop influences the global structure and diversity of the interaction surface of the gp120 outer domain to CD4 binding and epitopes exposure PubMed
env Individual gp120-CD4 bonds undergo rapid destabilization and this destabilization is significantly enhanced by the coreceptor CCR5, not by CXCR4 PubMed
env Association and clustering of CD4-CXCR4 induced by HIV-1 gp120 requires moesin-mediated anchoring of actin in the plasma membrane PubMed
env Interaction of the X4-tropic protein HIV-1 gp120 with CD4 augments ezrin and moesin phosphorylation in human permissive T cells, thereby regulating ezrin-moesin activation PubMed
env HIV-1 gp120 isolated from southern African HIV type 1 subtype C exhibits high-affinity binding to CD4 and the Cys228-Cys239 disulfide bond of gp120 is required for the high-affinity binding to CD4 PubMed
env Antibodies to LFA-3 block the early stages of HIV-1 infection by cell-free virus following HIV-1 gp120 binding to CD4 PubMed
env The binding of HIV-1 gp120 to CD4 molecules on T cells interrupts the sequential cascade of intercellular interactions involving antigen/MHC class II-TCR/CD4, CD40L-CD40, and B71-CD28 PubMed
env Alpha-defensins inhibit the binding of HIV-1 gp120 to CD4 through interaction with the D1 domain of CD4 PubMed
env The V3 domain of HIV-1 gp120 induces associations between CD4 and CCR5 receptors in cholesterol-rich microenvironments PubMed
env Binding gp140 to the synthetic CD4-mimicking mini protein leads to an outward domain shift of the three gp120 subunits, which diminishes gp120-gp41 interactions PubMed
env D279 in the C2 region and N362 in the C3 region of HIV-1 gp120 augment the gp120-CD4 interaction PubMed
env HIV-1 gp120 drastically reduces the ratio of CD4 dimers/monomers PubMed
env Maleic anhydride-modified ovalbumin inhibits HIV-1 entry by targeting both gp120 on HIV-1 virions and CD4 receptor on the host cells PubMed
env Palmitic acid analog 2-bromopalmitate (2-BP) efficiently binds to CD4 leading to the inhibition of gp120-to-CD4 binding PubMed
env HIV-1 gp120 interacts with CD4 to cause apoptosis in human mesenchymal stem cells PubMed
env A fusion of the CD4- and CCR5-mimetic peptides, DM1, binds gp120 and neutralizes R5, R5X4, and X4 HIV-1 isolates comparably to CD4 PubMed
env Griffithsin (GRFT) interaction with gp120 exposes the CD4 binding site by binding the glycan at position 386 PubMed
env The ability of thioredoxin, a protein disulfide isomerase (PDI), to reduce the disulfide bond in CD4 is enhanced in the presence of HIV-1 gp120 PubMed
env Sphingomyelinase inhibits viral fusion after the engagement of HIV-1 gp120 with CD4 and this inhibition is dependent on CD4 expression levels PubMed
env Tick salivary protein Salp15 prevents gp120-CD4 interaction at least partially through its direct interaction with the envelope glycoprotein in the C1 domain of gp120 PubMed
env HIV-1 gp120 with T257S/S375W double mutation is stabilized into the CD4-bound state, with increasing relative fixation between core, full-length monomeric, and full-length trimeric versions of gp120 PubMed
env Competition assays with CD4 and mAbs suggest that SP-A inhibits infectivity by occlusion of the CD4-binding site on gp120 PubMed
env In resting CD4 T cells, only the HIV envelope-mediated entry, but not the VSV-G-mediated endocytosis, can lead to viral DNA synthesis and nuclear migration PubMed
env In a CD4-bound state, gp120 elements proximal to the gp41 interface complete a 7-stranded beta-sandwich, which appeared invariant in conformation PubMed
env Co-expression of CD4 and DC-SIGN in Raji cells promotes internalization and intracellular retention of HIV-1 through interaction with HIV-1 gp120 PubMed
env Expression of CD4 on Raji B cells strongly inhibits DC-SIGN-mediated HIV-1 transmission to T cells, presumably through interaction with HIV-1 gp120 PubMed
env CCR5- or CXCR4-tropic HIV-1 induce Indoleamine 2,3-dioxygenase (IDO) in plasmacytoid dendritic cells and this induction is inhibited by the blockade of gp120/CD4 interactions with antibodies to CD4 PubMed
env Substitution of highly conserved isoleucine with methionine at position 424 in the C4 domain of gp120 confers enhanced neutralization sensitivity to plasma antibodies and increases its interaction with sCD4 but not with CCR5 PubMed
env HIV-1 infections originating from cell-free virus by CD4/gp120 interactions decrease strongly in the presence of antiretrovirals tenofovir and efavirenz whereas infections involving cell-to-cell spread are markedly less sensitive to the drugs PubMed
env Bile salt-stimulated lipase (BSSL), a Lewis X (LeX)-containing glycoprotein found in human milk, binds to DC-SIGN and inhibits the interaction of gp120 with CD4 PubMed
env The disulfide cross-linking interaction between gp120 and PDI is enhanced by CD4 protein PubMed
env CD4 binding results in a major reorganization of the gp120 trimer, causing an outward rotation and displacement of each gp120 monomer PubMed
env Focal adhesion kinase (FAK), CD4, and HIV-1 gp120 co-localize in T cells. The formation of FAK-CD4 complex is induced by gp120 PubMed
env Epigallocatechin gallate (EGCG) purified from the green tea catechin inhibits attachment of HIV-1 glycoprotein 120 to the CD4 molecule on T cells PubMed
env H66N change in gp120 stabilizes the HIV-1 envelope glycoprotein complex once the CD4-bound state is achieved and decreases the probability of CD4-induced inactivation PubMed
env Two potentially flexible topological layers (layers 1 and 2) in the gp120 inner domain (layer 1-layer 2) interactions strengthen gp120-CD4 binding by reducing the off rate when CD4 makes initial contact with the gp120 outer domain PubMed
env HIV-1 gp120-induced Ca(2+) fluxing is CD4 dependent and coreceptor specific, and is mediated by the CCR5 and CXCR4 coreceptors PubMed
env Virions carrying both HIV-1 R5 env and VSV-G can fuse to naive CD4+ T cells because CD4 binding allows viral uptake PubMed
env Genistein, tyrosine kinase inhibitor, inhibits cell fusion between macrophages and HIV-1 Env expressing cells. Genistein treatment does not change CD4 or CCR5 surface expression and has no effect on gp120-CD4-CCR5 complex formation PubMed
env Studies by sequential (SAP) and competitive (CAP) antigen panning methodologies show that some antibodies bind better to gp120-CD4 complexes than to gp120 alone PubMed
env The ability of gp120 to inhibit SDF-1alpha-induced chemotaxis is mediated by the CD4 receptor and Lck signaling PubMed
env Subtype C gp120 isolates carrying I309L enhance utilization of CD4 but do not affect the ability to use CCR5 PubMed
env Virological synapse-mediated cell-to-cell HIV-1 transfer is dependent upon gp120/gp41 and CD4 interactions and is more efficient than that of a cell-free mode of uptake, yet the presence of the full CD4 cytoplasmic tail is not essential for the process PubMed
env Siva-1 sensitizes CD4-positive T-cells to HIV-1 gp120/gp41-induced apoptosis. The Siva-1-mediated sensitization on CD4-positive T-cells shows significant activation of caspase-3, -8, and -9 PubMed
env The V1-V3 region of a brain-derived HIV envelope glycoprotein plays a crucial role in determining the virus' low CD4 dependence and increased macrophage tropism, as well as its augmented fusogenicity and reduced sensitivity to the inhibitor BMS-378806 PubMed
env HIV-1 gp120 hydrogen bond interactions among transmembrane residues Y108, E283, and Y251, are crucial for HIV-1-gp120/sCD4 complex binding and HIV-1 fusion. HIV-1 gp120 binding to CCR5 disrupts these interhelix hydrogen bond interactions PubMed
env Deletion of the HIV-1 gp120 major variable regions (V1/V2/V3) stabilizes gp120 core proteins into the conformation recognized by CD4 PubMed
env A synthetic CD4-mimetic peptide conjugating with a heparan sulfate dodecasaccharide binds to gp120 and induces the exposure of the coreceptor binding domain available for interaction with the oligosaccharide PubMed
env HIV-1 gp120 promotes filamin binding to both CD4 and CXCR4 PubMed
env CIITA-mediated enhancement of HIV-1 infection is gp120/gp41/CD4-dependent and occurs at the early steps in the infection cycle PubMed
env Elimination of the CD4 domain 2 disulfide bond (Cys130-Cys159) by mutation enhances HIV-1 gp120/gp41-mediated cell-cell fusion and virus entry PubMed
env Thioredoxin cleaves the gp120 disulfide bond (Cys296-Cys331) in the V3 domain and the cleavage is enhanced by CD4-expressing cells PubMed
env The cis expression of DC-SIGN on multiple lymphoid cell lines enables more efficient entry and replication of CXCR4-tropic and CCR5/CXCR4 dual-tropic HIV-1 through its binding to the HIV-1 gp120-CD4-CXCR4 complex PubMed
env HIV-1 gp120 specifically recognizes the C-terminal heparin-binding domain of fibronectin (Fn) and this binding inhibits the interaction of gp120 with soluble CD4 PubMed
env Apoptosis of CD4+ lymphocytes induced by HIV-1 gp120 cross-linking to CD4 is inhibited by IL-12 PubMed
env HIV-1 envelope glycoprotein gp120 binds to the cell surface receptor CD4 or soluble CD4; the carbohydrates present on gp120 are necessary for CD4 binding during HIV-1 entry PubMed
env HIV-1 envelope glycoproteins gp120 and gp160 directly and specifically impair the CD3/TcR-mediated activation of phospholipase C (PLC) via the CD4 molecule in uninfected T cells PubMed
env Galectin-1, a dimeric beta-galactoside-binding protein, promotes infection with CCR5-tropic, CXCR4-tropic, and CCR5/CXCR4 dual-tropic HIV-1 variants by facilitating attachment of HIV-1 gp120 to CD4 at the cell surface PubMed
env The binding of HIV-1 gp120 to CD4+-permissive cells increases the level of acetylated alpha-tubulin in a CD4-dependent manner; overexpression of Histone Deacetylase 6 (HDAC6) inhibits the acetylation of alpha-tubulin and prevents HIV-1-cell fusion PubMed
env Griffithsin isolated from an aqueous extract of the red alga Griffithsia species blocks CD4-dependent HIV-1 gp120 binding to receptor-expressing cells and binds to viral coat glycoproteins (gp120, gp41, and gp160) in a glycosylation-dependent manner PubMed
env HIV-1 gp120-CD4 interaction is necessary to repress HIV-1 long terminal repeat-dependent luciferase activity; the cytoplasmic domain of CD4 is found to be required for this effect to occur PubMed
env Binding of HIV-1 gp120 to CD4 molecules in cells results in the association of Lck and Raf-1, which is abolished by preincubation of the virus with soluble CD4 PubMed
env The fusion of insulin-like growth factor I (IGF I) with stromal cell-derived factor I or alpha1 proteinase inhibitor has the capacity to compete with the binding of HIV-1 gp120 to CD4 receptor PubMed
env Phorbol myristate acetate (PMA) pretreatment of CD4+ cells prevents subsequent HIV-1 gp120-induced downregulation of CD4 receptor molecules PubMed
env Expression of the HIV-1 envelope gene in CD4+ T cell lines and binding of HIV-1 gp120 to CD4 is sufficient for the induction of apoptosis PubMed
env Combinations of CD4-based molecules and antibodies to HIV-1 gp120 and/or gp41 inhibit cell fusion formation mediated by the interaction of CD4 to gp120 PubMed
env Following incubation with a soluble form of CD4, gp120 of highly purified HIV-1 preparations is cleaved without addition of exogenous proteinase, yielding two proteins of 50 and 70 kDa; this cleavage likely occurs in the gp120 V3 loop PubMed
env Mutants with amino acid changes in the V1/V2 region (residues 131-196) of the HIV-1 gp120 are able to bind CD4 but are deficient in syncytium formation and/or virus entry PubMed
env Release of neurotoxins from monocytes through HIV-1 gp120 stimulation involves CD4 receptors; toxin production can be inhibited either by a monoclonal antibody to the CD4-binding region of gp120 or by soluble CD4 receptors PubMed
env Calcium ions are required for cell fusion mediated by interactions between CD4 and HIV-1 gp120/gp41; EDTA and EGTA block cell fusion in culture media containing calcium ions PubMed
env The third complementarity-determining region (CDR3; residues 79-96) within domain 1 of the human CD4 molecule plays a critical role in membrane fusion mediated by the interaction of CD4 with HIV-1 gp120 PubMed
env Binding of HIV-1 gp120 to the CD4 receptor molecule results in co-stimulation of CD3-induced T cell activation PubMed
env HIV-1 gp120-mediated CD4 engagement is involved in the induction of susceptibility of primary human T lymphocytes to CD95-mediated apoptosis through ezrin phosphorylation and ezrin-to-CD95 association PubMed
env HIV-1 gp120 interacts with CD4 and alphavbeta3 in peripheral blood monocyte-derived macrophages; neutralizing antibodies against the alphavbeta3 integrin interfere with the coprecipitation of alphavbeta3 with an anti-gp120 antibody PubMed
env Human C" beta strand (amino acids 42-47) of CD4, particularly Phe-43, plays a crucial role in HIV-1 coreceptor function as well as in HIV-1 gp120-CD4 binding capacity PubMed
env The chemokine receptor CCR5 is posttranslationally modified by sulfation of its N-terminal tyrosines; sulfated tyrosines contribute to the binding of CCR5 to MIP-1 alpha, MIP-1 beta, and HIV-1 gp120/CD4 complexes and to the ability of HIV-1 to enter cells PubMed
env The inhibition of IL-2R expression and proliferation induced by the interaction of CD4 with HIV-1 envelope glycoprotein gp120 is correlated with the inhibition of expression and activation of Janus kinase JAK3 PubMed
env Antibodies to specific epitopes of HIV-1 gp120 block the interaction of CCR5 with the gp120/CD4 complex, suggesting that a CD4-mediated conformational change in gp120 is required for subsequent binding to CCR5 PubMed
env A specific interaction between CD4 and HIV-1 gp120 is required for phosphorylation of CD4, which could involve protein kinase C PubMed
env Amino acid residues 42-49 and 54-57 in the V1 region of CD4 are involved in the interaction of CD4 with both HIV-1 gp120 and class II major histocompatibility complex molecules PubMed
env Mutations at four locations (amino acids 29, 59-64, 77-81, and 85) outside the antigen-complementarity-determining region (CDR2)-like sequence of CD4 markedly affect HIV-1 gp120 binding PubMed
env Removal of the N-linked sugars on HIV-1 gp120 by endoglycosidase H treatment results in deglycosylated proteins that are unable to bind to CD4, suggesting that glycosylation contributes to the ability of gp120 to bind to CD4 PubMed
env Deletion analysis shows that amino acid regions 82-95, 386-389, 424-432, and 487-499 constitute a part of the HIV-1 gp120 binding region to CD4 PubMed
env HIV-1 gp120/160 deglycosylated by Endo H and Endo F still binds to CD4, indicating that the carbohydrates of gp120/160 do not play a significant role in the in vitro binding to CD4 PubMed
env HIV-1 gp120 suppresses T and B cell activation and the expression of cytolytic activities through its interaction with CD4 PubMed
env HIV-1 gp120 and class II MHC binding sites of CD4 are distinct and can be separated PubMed
env A single amino-acid change (cysteine 402 or tryptophan 432) in HIV-1 gp120 can abrogate CD4 binding PubMed
env Apoptosis induced by HIV-1 gp120/CD4 cross-linking in Th1 clones is inhibited by anti-CD95 or anti-CD95L neutralizing monoclonal antibodies, as well as by a specific interleukin-1 beta converting enzyme (ICE) inhibitor PubMed
env IL-16 induces rapid translocation of PKC from the cytosol to the membrane in CD4+ cells; PKC inhibitors completely block IL-16-induced lymphocyte migration as well as the motile response induced by HIV-1 gp120 and anti-CD4 antibody binding to CD4 PubMed
env Small molecules exhibit strong anti-HIV-1 activity by binding specifically to both HIV-1 gp120 and/or cell surface receptors (CD4, CCR5, CXCR4) and prevent gp120/CD4/CCR5 and gp120/CD4/CXCR4 complex formation and cell-cell fusion PubMed
env CD4 downregulation by the treatment of macrophages with HIV-1 gp120 is mediated through the induction of endogenous TNF-alpha PubMed
env A CD4 peptide (amino acids 74-95) inhibits the binding of gp120 to CD4+ human lymphoblastic leukemia (CEM) cells PubMed
env Through binding to cell surface CD4, both HIV-1 gp120 and gp160 inhibit syncytia formation between HIV-1-infected cells and CD4+ cells PubMed
env Chimpanzee CD4 molecules bearing the human amino acid at position 87 support syncytium formation, while human CD4 molecules bearing the chimpanzee residue at position 87 do not; HIV-1 gp120 binding to CD4 is not affected by the substitution at position 87 PubMed
env Expression of a soluble CD4 mutant molecule lacking transmembrane and cytoplasmic domains blocks secretion of HIV-1 gp120 and surface expression of HIV-1 gp120 and gp41 from the endoplasmic reticulum PubMed
env Binding of recombinant soluble CD4 (sCD4), the purified V1 domain of sCD4, or neutralizing antibodies to the HIV-1 surface glycoprotein gp120 on virions results in rapid dissociation of gp120 from its complex with the transmembrane glycoprotein gp41 PubMed
env Small molecules, termed N-carbomethoxycarbonyl-prolyl-phenylalanyl benzyl esters (CPFs), block the binding of gp120 to CD4, but do not interfere with the binding of CD4 to class II major histocompatibility complex molecules PubMed
env HIV-1 gp120 with substitution of cysteine's 296, 331, 418 or 445 on fails to bind to CD4 PubMed
env The N-terminal region of HIV-1 gp120 contains conserved residues (amino acids 56-62 and 108-116) critical for binding to CD4 PubMed
env Changes in two hydrophobic regions (Thr-257 and Trp-427) and two hydrophilic regions (Asp-368, Glu-370, and Asp-457) of HIV-1 gp120 result in significant reductions in CD4 binding PubMed
env Soluble CD4 can bind to HIV-1 gp120 and block HIV-1 infectivity PubMed
env Expression of the human CD4 receptor in murine T-cells is sufficient for syncytia formation with HIV-1 envelope expressing cells and entry of MLV/HIV pseudotyped retroviral vectors, suggesting that the murine CXCR4 is a functional coreceptor PubMed
env CD4(+)CD45RO(+) cells display high HIV-1 gp120-binding capacity, whereas CD4(+)CD45RO(-) cells show undetectable HIV-1 gp120 binding PubMed
env The physiological levels of cell-surface CD4 interfere with HIV-1 replication in T cells by a mechanism that inhibits HIV-1 gp120 envelope incorporation into viral membranes PubMed
env Syncytial apoptosis mediated by the fusion of cells expressing HIV-1 gp120 with cells expressing the CD4/CXCR4 receptor/coreceptor complex causes phosphorylation of p53 on serine 15 and Bax upregulation PubMed
env Mutation of two basic amino acids Lys46 and Arg59 in CD4 dramatically disrupts its ability to bind HIV-1 gp120 PubMed
env The interaction between exposed cyclophilin A (CypA) and cell surface heparans represents the initial step of HIV-1 attachment and is a necessary step for HIV-1 gp120 binding to CD4 PubMed
env CD4-expressing human T cell lines induce significant and rapid conformational changes in gp120-gp41 from T cell-tropic HIV-1 strains, and little conformational changes in gp120-gp41 from macrophage-tropic HIV-1 strains PubMed
env Binding of HIV-1 gp120 to CD4 receptor induces p56lck activation and zeta-chain (TCR) associated protein kinase 70kDa desensitization independent of TCR tyrosine phosphorylation PubMed
env Pretreatment of HIV-1 infected cells with TNF alpha augments syncytia formation mediated by the interaction of HIV-1 gp120 with cell surface CD4 molecules PubMed
env Interaction of HIV-1 gp120 with cell-associated CD4 leads to the induction of IFN alpha; preincubation of cells with anti-CD4 or the presence of soluble CD4 during incubation inhibits IFN alpha induction PubMed
env A high affinity interaction between the HIV-1 glycoprotein gp120/gp41 complex and the cellular receptor CD4 is necessary for both virus-cell and cell-cell fusion; the V3 region (amino acids 301-336) of gp120 and gp41 amino terminus are involved in fusion PubMed
env Cleavage at position R315 of HIV-1 gp120 by thrombin is enhanced by soluble CD4 binding PubMed
env Two disulfide bonds linking cysteine residues at positions 378 and 445 and positions 385 and 418 in the carboxyl terminus of HIV-1 gp120 contribute to CD4 binding PubMed
env Amino acid residues (102-126) and (425-452) of HIV-1 gp120 contribute to the binding site for CD4 and are expected to be juxtaposed in the folded gp120 chain PubMed
env Crosslinking of HIV-1 gp120 on human CD4+ T cells followed by signaling through the TCR results in activation-induced apoptosis PubMed
env LFA-1 adhesion molecules are not involved in the early stages of cell membrane fusion mediated by the interaction of gp120 with CD4 PubMed
env Down modulation of the interaction between HIV-1 gp120 and CD4 by TPA is blocked by protein kinase C (PKC) inhibitors, suggesting PKC may play an important role in HIV-1 infection PubMed
env 12-O-tetradecanoylphorbol-13-acetate (TPA) down-modulates the expression of CD4, which is essential for syncytia formation through interaction with the HIV-1 envelope protein gp120 PubMed
env Glycolipids such as galactosylceramides, sulfogalactoceramides, globotriosylceramide, and gangliosides play an important role as HIV-1 fusion cofactors following the interaction of CD4 and HIV-1 gp120 PubMed
env Gross cystic disease fluid protein-15 (GCDFP-15) binds to CD4, a T-cell co-receptor involved in antigen recognition, thereby inhibiting the ability of the receptor to interact with the HIV-1 envelope protein gp120 PubMed
env Contact of CD4+ T cells with HIV-1 infected or HIV-1 gp120-expressing cells induces PARP hydrolysis, which leads to the cleavage of 116 kDa PARP into two fragments PubMed
env CD4-p56Lck interaction is required for HIV-1 gp120-induced nuclear translocation of NF-kappaB in HeLa cells PubMed
env Adsorption of multivalent gp120-containing HIV-1 virion particles into CD4+ T lymphocytes results in segregation of CD4 and CXCR4 into distinct lipid micro domains PubMed
env Protein-disulfide isomerase (PDI) cleaves disulfide bonds in recombinant HIV-1 envelope glycoprotein gp120, and gp120 bound to the surface receptor CD4 undergoes a disulfide reduction that is prevented by PDI inhibitors PubMed
env A fusion protein between HIV-1 gp120 hepatitis B surface antigen (HBsAg) is capable of spontaneous assembly into virus-like particles and exhibits high affinity binding to CD4 PubMed
env Retrocyclin binds to soluble CD4 and HIV-1 gp120, colocalizes with CD4, CXCR4, and CCR5, and inhibits replication of CCR5-tropic and CXCR4-tropic strains of HIV-1 in human cells, presumably through inhibition of gp120-CD4 binding PubMed
env The level of HIV-1 gp120-mediated syncytium formation and infectivity is enhanced in the presence of neuraminidase (NA) and involves the interaction between gp120, CD4, and chemokine coreceptors PubMed
env The CCR5 chemokine receptor is required for the entry of macrophage-tropic HIV-1 into target cells; the HIV-1 gp120-CD4 complex binds CCR5, which inhibits the binding of the natural CCR5 ligands macrophage inflammatory protein (MIP)-1alpha and MIP-1beta PubMed
env CXCR4, a 45kDa cellular membrane protein, interacts with the cell surface HIV-1 gp120-CD4 complex and acts as a coreceptor to preferentially support T cell line-tropic HIV-1 Env-mediated cell fusion and HIV-1 infection PubMed
env CD26 (dipeptidyl peptidase IV) cleaves the highly conserved V3 loop of HIV-1 gp120 and functions as a cofactor for entry of HIV-1 in CD4+ human cells; coexpression of human CD4 and CD26 in murine NIH 3T3 cells renders them permissive to HIV-1 PubMed
env Cells expressing a chimeric molecule consisting of the first 177 residues of CD4 attached to residues from the hinge, transmembrane, and cytoplasmic domains of CD8 are susceptible to fusion with cells expressing HIV-1 gp120 PubMed
env Several polyanionic anti-HIV compounds, including dextran sulfate, pentosan polysulfate, heparin, aurintricarboxylic acid (ATA), suramin, and Evans blue, interact with HIV-1 gp120 to block the binding of gp120 to CD4 PubMed
env A 287 residue variant of HIV-1 gp120 (ENV59) missing 197 amino acids binds to CD4 with high affinity PubMed
env Cell-cell contact between T cells expressing HIV-1 gp120/gp41 and other T cells expressing CD4 receptors leads to the rapid accumulation of cyclin B and tyrosine-hyperphosphorylated p34cdc2 (cdk1) kinase, indicative of cell cycle arrest at G2 phase PubMed
env HIV-1 envelope protein gp120 can specifically inhibit CD4-dependent class II MHC-restricted T cell response to Antigens PubMed
env Monoclonal antibodies (MAbs) to defined peptide epitopes or N-linked glycans in HIV-1 gp120 inhibit the binding of gp120 to CD4 and exhibit neutralizing activities against HIV-1 PubMed
env 95- and 25-kDa peptides derived from the disulfide bond reduction of HIV-1 gp120 bind to human CD4 PubMed
env The first two domains (amino acid residues 1-177) of human CD4 bind effectively to HIV-1 gp120, and most residues interacting with gp120 lie within amino acids 21-64; the COOH-terminal half of the molecule is not necessary PubMed
env Amino acid sequences 397-439 in HIV-1 gp120 are directly involved in the binding of gp120 to the CD4 receptor PubMed
env Synthetic peptides as agonists of the HIV-1 envelope glycoprotein gp120 or CD4 receptor block the binding of gp120 and CD4 PubMed
env Anti-CD4 antibodies are capable of neutralizing HIV-1 strains or blocking the binding of HIV-1 envelope glycoprotein gp120 and cell surface receptor CD4 PubMed
env HIV-1 gp120 induces the dissociation of p56lck from CD4 and the downregulation of CD4 from the cellular surface PubMed
env Cleavage of HIV-1 gp120 with trypsin at residue 432 destroys CD4 binding PubMed
env Inhibition of HIV-1 binding to CD4 by suramin is reversed by human albumin, suggesting that only free suramin has antiviral properties PubMed
env HIV-1 gp120 stimulates monocytes to release TNF-alpha, IL-1 beta, IL-6, and granulocyte-macrophage-CSF, and this effect can be blocked with soluble CD4 PubMed
env T-tropic HIV-1 gp120s are capable of priming phorbol ester (PMA) induced co-down-modulation of gp120 complexes with tailless CD4 by interacting with CXCR4, whereas M-tropic gp120 are not, even in the presence of CCR5 PubMed
env Antibodies to specific epitopes of the CCR5 or CXCR4 chemokine receptors inhibit the entry of M-tropic, T-tropic, or dual-tropic HIV-1 into target cells by blocking the interaction of the receptors with the HIV-1 gp120/CD4 complex PubMed
env CD38 expression blocks lymphocyte susceptibility to HIV-1 infection by inhibiting HIV-1 gp120/CD4-dependent viral binding to target cells PubMed
env HIV-1 gp120 induces CD4 association with lymphocyte surface molecules CD3, CD11a, CD27, CD45RA, CD45RB, CD45RO, CD49d, CD38, CD26, CD59, CD95 and class I MHC molecules PubMed
env HIV-1 gp120 induces a specific phospholipase A2 (PLA2) activation in lymphocytes through binding to CD4, but this effect is not sufficient to accomplish virus/cell fusion PubMed
Envelope transmembrane glycoprotein gp41 env A bivalent HIV-1 inactivator 2DLT by linking the D1D2 domain of CD4 to HIV-1 fusion inhibitor T1144 induces the formation of the gp41 prehairpin fusion-intermediate (PFI) and the T1144 domain in 2DLT then binds to the exposed PFI PubMed
env HIV-1 induces an elongated phenotype in infected CD4+ T cells. These HIV-infected T cells tether to other lymph node CD4+ cells and form syncytia through gp120/gp41, and migrate to distant tissues to disseminate PubMed
env A single Y681H substitution in HIV-1 gp41 increases the gp120-CD4 binding and enhances infectivity in low CD4 expressing cells PubMed
env HIV-1 gp120 and gp41 form a transitional complex with the CD4 receptor and CCR5/CXCR4 coreceptors during virus-cell and cell-cell membrane fusion PubMed
env A truncated cytoplasmic domain of 27 amino acids in HIV-1 gp41 can expose highly conserved domains involved in both HIV-1 coreceptor and CD4 binding PubMed
env Binding gp140 to the synthetic CD4-mimicking mini protein leads to an outward domain shift of the three gp120 subunits, which diminishes gp120-gp41 interactions PubMed
env A point mutation (V38E) in the gp41 region of HIV-1 abolishes HIV-1-mediated apoptosis by CASP3 and minimizes CD4 loss in humanized mice without altering viral replication PubMed
env In resting CD4 T cells, only the HIV envelope-mediated entry, but not the VSV-G-mediated endocytosis, can lead to viral DNA synthesis and nuclear migration PubMed
env The HIV-1 transmembrane glycoprotein gp41 is an amino acceptor and donor substrate for transglutaminase in vitro; soluble CD4 can block the transglutaminase-catalyzed incorporation of the polyamine spermidine into HIV-1 gp41 PubMed
env Virological synapse-mediated cell-to-cell HIV-1 transfer is dependent upon gp120/gp41 and CD4 interactions and is more efficient than that of a cell-free mode of uptake, yet the presence of the full CD4 cytoplasmic tail is not essential for the process PubMed
env Siva-1 sensitizes CD4-positive T-cells to HIV-1 gp120/gp41-induced apoptosis. The Siva-1-mediated sensitization on CD4-positive T-cells shows significant activation of caspase-3, -8, and -9 PubMed
env CIITA-mediated enhancement of HIV-1 infection is gp120/gp41/CD4-dependent and occurs at the early steps in the infection cycle PubMed
env Elimination of the CD4 domain 2 disulfide bond (Cys130-Cys159) by mutation enhances HIV-1 gp120/gp41-mediated cell-cell fusion and virus entry PubMed
Gag, Pr55 gag HIV-1 Gag/p24 co-localizes with CD4 in the intracellular CD4+ compartments in primary T lymphocytes PubMed
gag HIV-1 Gag-positive uropods form contacts enriched in CD4 PubMed
Nef, p27 nef HIV-1 Nef clones, isolated from plasma of elite controllers (EC) and chronic progressors (CP), show significantly lower CD4 downregulation activity in EC than that in CP PubMed
nef HIV-1 Nef clones obtained from chronic patients infected with HIV-1 subtypes A, B, C or D show a functional hierarchy of subtype B > A/D > C for Nef-mediated CD4 downregulation PubMed
nef Functional ARF1 is required for HIV-1 Nef-dependent endogenous HLA-A2 and CD4 downregulation in HIV-infected primary T cells PubMed
nef Interaction of HIV-1 Nef with AP-2 alpha-sigma dimer is required for Nef-mediated CD4 downregulation. The dileucine L164L165 and M168L170 motifs bind to the sigma unit, while the acidic motif E174 and D175 binds to the alpha unit PubMed
nef The hydrophobic region (residues 168-173) downstream of the HIV-1 Nef dileucine motif (L164L165) is involved in HIV-1 Nef-mediated CD4 downregulation PubMed
nef HIV-1 Nef enhances the infectivity of CD4-chemokine receptor-pseudotyped HIV-1 for target cells expressing HIV-1 Env. Virus-producing cells expressing dominant-negative dynamin 2 (K44A) selectively inhibits these receptor-pseudotyped virions PubMed
nef CD4 and MHC-1 downregulation are highly conserved in primary HIV-1 Nef alleles from brain and lymphoid tissues, but Pak2 activation is highly variable PubMed
nef HIV-1 Nef mutants LLAA and delta12-39 significantly impair downregulation of CD4. Nef LLAA mutant fails to interact with the endocytic machinery and Nef delta12-39 mutant lacks the interaction with the Nef-associated kinase complex PubMed
nef HIV-1 Nef drastically reduces the ratio of CD4 dimers/monomers PubMed
nef beta-COP as a cellular cofactor is required for HIV-1 Nef-mediated HLA-A2, CD4, and CD8 downregulation PubMed
nef Single mutation at the ubiquitination residue K144 or at the tyrosine motif Y202F203 in HIV-1 Nef greatly impairs Nef-mediated CD4 downregulation PubMed
nef TPCK and TLCK alkylation reagents chemically modify HIV-1 Nef at residues Cys55 and Cys206. Cys55 modification reduces the strength of the interaction between Nef and CD4 tail peptide PubMed
nef HIV-1 Nef expression from unintegrated HIV-1 DNA downregulates the surface levels of CD4, CCR5, and CXCR4 on T-lymphocytes and monocytes PubMed
nef HIV-1 Nef interacts with CD4 in living cells PubMed
nef HIV-1 Nef targets CD4 to CD63-containing lysosomes for Nef-induced degradation of CD4, which requires the VPS4-mediated ESCRT machinery PubMed
nef K295, K297, K298, and R340 basic residues on the AP-2 alpha subunit are required for its binding to HIV-1 Nef. The K297 and R340 residues are required for Nef-induced CD4 downregulation and the cooperative assembly of a Nef-CD4-AP-2 complex PubMed
nef L37, P78 and E177 residues of HIV-1 Nef are required for its effect on CD4 internalization and recycling but dispensable for Nef-induced retention and degradation of intracellular CD4 PubMed
nef HIV-1 Nef-Vpr fusion proteins are efficiently incorporated into HIV-1 particles and possess CD4 downregulation activity in target cells PubMed
nef An intact Nef dimerization interface, including the multiple hydrophobic (I109, L112, Y115, and F121) and electrostatic (R105 and D123) residues, is required for Nef-induced CD4 downregulation in cells PubMed
nef An intact hydrophobic interface (residues I109, L112, Y115, and F121) is essential for HIV-1 Nef dimerization in cells and is required for Nef-mediated CD4 receptor downregulation PubMed
nef HIV-1 Vpr increases expression of Nef protein from integrase-defective HIV-1. The Vpr-mediated expression of Nef from IN-minus HIV-1 results in CD4 downregulation PubMed
nef Expression of p56(lck) in nonlymphoid CD4-expressing cells restores the ability of Nef in order to increase the internalization rate of CD4 PubMed
nef HIV-1 Nef downregulates CD4 expression on the surface of Jurkat cells and blocks the CD3 signaling pathway; mutations at amino acids 174 and 175 reduce the ability of Nef to downregulate CD4 expression PubMed
nef The HIV-1 Nef mutant F12-HIVNef, containing three rare amino acid substitutions, G(140)E, V(153)L and E(177)G, represses Nef-induced accelerated rates of CD4 internalization and p62NAK activation PubMed
nef A dileucine motif in Nef is required for CD4 downregulation and for interaction with clathrin adaptor complexes AP-1 and AP-2, which are responsible for recruiting sorted proteins into clathrin-coated pits PubMed
nef Deletion of the 19 N-terminal amino acids, including the myristoylation signal from HIV-1 Nef inhibits both MHC-I and CD4 downregulation while preserving most CTL, T-helper and B-cell epitopes PubMed
nef Different levels of CD4 modulation are induced by different HIV-1 Nef proteins derived from HIV-1 infected adults and children PubMed
nef The functional ability of HIV-1 Nef to downregulate CD4, but not MHC class I, is associated with Nef-mediated enhancement of HIV-1 pathogenicity in severe combined immunodeficiency (SCID) mice implanted with human fetal thymus and liver PubMed
nef CD4 downregulation by HIV-1 Nef enhances the efficiency of HIV-1 replication in both activated human primary T lymphocytes and lymphoid tissues; Nef-induced CD4 downregulation correlates with severe depletion of CD4+ T cells in lymphoid tissues PubMed
nef Expression of HIV-1 Nef in human monocyte-derived dendritic cells using an adenovirus based delivery system decreases CD4 levels, but has no effect on class I MHC PubMed
nef HIV-1 Nef downregulates CD4 in Jurkat cells in a concentration-dependent manner PubMed
nef HIV-1 Nef mutants C142A and K158A/E160G exhibit a temperature-dependent ability to downregulate CD4 PubMed
nef HIV-1 Nef downregulates CD4 rapidly during the early phase of virus infection, whereas HIV-1 Vpu and Env function late in the infection; in primary cells, down-modulation of CD4 has a stronger dependence on Nef function for reducing cell surface CD4 PubMed
nef High levels of CD4 on the surface of an HIV-1 producing cell block viral infectivity by interfering with incorporation of HIV-1 envelope into the virion; HIV-1 Nef and Vpu inhibit this block by downregulating CD4 from the cell surface PubMed
nef Mutational analysis of HIV-1 Nef shows that a membrane targeting domain (residues 2-7) and a conserved glutamic acid-rich segment (residues 60-71) are required for CD4 downregulation but not for viral infectivity enhancement PubMed
nef HIV-1 Nef downregulates cell surface expression of CD4 in CEM Nef+ cells by promoting the accumulation of CD4 in an acidic early endosome PubMed
nef An isoleucine residue at position 410 and two leucine residues at positions 413 and 414 in CD4 are required for HIV-1 Nef-mediated CD4 downregulation in cells PubMed
nef Two distinct regions within HIV-1 Nef, amino acid residues 96-144 and 175-186, are required for CD4 downregulation in cells PubMed
nef The presence of an alpha-helix in CD4, which extends from residues Gln403 to Arg406, promotes the binding of CD4 to HIV-1 Nef PubMed
nef Yeast two-hybrid assays show that a nearly complete HIV-1 Nef protein is required for binding to the CD4 cytoplasmic domain (residues 394-416), and the dileucine motif in CD4 (residues 413-414) is essential for this direct interaction PubMed
nef Solution NMR spectroscopy studies show a 13 amino acid peptide (residues 407-419) derived from the CD4 cytoplasmic domain binds directly to HIV-1 Nef in a manner that involves amino acid residues 57-59, 95-97, 106, and 110 in Nef PubMed
nef CEM cells stably transfected with a replication-defective provirus of HIV-1 that has a rev-splicing mutation and expresses an intact nef gene have markedly reduced cell surface expression of CD4 PubMed
nef HIV-1 Nef-mediated downregulation of CD4 is induced by an accelerated dissociation of the T-cell tyrosine kinase Lck and CD4, and a decrease in the half-life of CD4 PubMed
nef A dileucine motif in the cytoplasmic domain of CD4 is involved in the association of CD4 with the tyrosine kinase Lck and the downregulation of CD4 by HIV-1 Nef, however Nef does not induce dissociation of Lck from CD4 in acutely HIV-infected cells PubMed
nef A dileucine motif in the cytoplasmic tail of CD4 is not required for HIV-1 Nef binding in insect cells, but is essential for Nef-induced CD4 downregulation PubMed
nef Experiments using both a recombinant HIV-1 Integrase-defective virus and a diketo acid Integrase inhibitor demonstrate that HIV-1 Nef expressed from extra chromosomal DNA (E-DNA) downregulates CD4 surface expression on primary CD4(+) T lymphocytes PubMed
nef The Nef protein from the primary virus isolate HIV-1 KS2 lacks two glutamic acid residues (EE154-5) and has a decreased ability to downregulate CD4 PubMed
nef HIV-1 expressing Nef proteins defective in CD4 downregulation activity retain wild-type levels of infectivity in single-round assays, but exhibit delayed replication kinetics and lower titers compared to the wild-type virus in monocyte-derived macrophages PubMed
nef PMA treatment of T cells expressing HIV-1 Nef, which downregulates CD4, restores cell surface CD4 up to 35%; mutations in the phosphorylation sites of the CD4 cytoplasmic tail (Ser408 and Ser415) abolish this effect of PMA PubMed
nef HIV-1 Nef-mediated CD4 downregulation is profoundly inhibited by the synergistic effect of Eps15DIII, a dominant negative mutant of Eps involved in endocytosis and RNA interference of AP-2 expression PubMed
nef Bioluminescence resonance energy transfer (BRET) and co-immunoprecipitation assays have been used to demonstrate the interaction of HIV-1 Nef and CD4 in intact human cells PubMed
nef HIV-1 group N and group O Nef alleles only weakly downregulate CD4, CD28, and class I and II MHC molecules PubMed
nef A dileucine motif in the CD4 cytoplasmic domain is required for its downregulation by HIV-1 Nef; cysteine residues in the cytoplasmic domain of CD4 are essential for the binding of Lck but are not required for Nef-induced downregulation PubMed
nef HIV-1 Nef induces drastic and moderate downregulation of CD4 and MHC-I in resting CD4(+) T lymphocytes, respectively, but markedly upregulates cell surface levels of the MHC-II invariant chain CD74 PubMed
nef HIV-1 Nef forms a ternary complex with ARF1 and beta-COP in endosomes, which facilitates Nef-induced downregulation and transport of CD4 to acidic late-endosomal compartments PubMed
nef HIV-1 Nef-induced CD4 degradation is regulated by a highly conserved diacidic-based motif in Nef that acts as a lysosomal targeting signal through the binding of beta-COP in endosomes PubMed
nef Nef from primary isolates of HIV-1 suppresses surface CD4 expression in human and mouse T cells PubMed
nef Transduction of the HIV-1 nef gene into murine cells expressing human, chimpanzee, or murine CD4 induces cell surface downregulation of all three molecules; the cytoplasmic domain of CD4 is required for its downregulation by Nef PubMed
nef In adult HIV-1 Nef transgenic mice, CD4 downregulation is found in CD4- and CD8-double positive thymocytes; co-localization of CD4 with a Golgi-specific marker indicates Nef interferes with CD4 intracellular trafficking PubMed
nef CD4 is downregulated by nef alleles isolated from peripheral blood leukocytes of HIV-1-infected individuals; Nef proteins with point mutations at positions Gly2, Asp36, Cys122, and Val148 exhibit different levels of CD4 downregulation PubMed
nef CD4 downregulation by HIV-1 Nef is independent of the level of CD4 mRNA expressed in cells and of the level of CD4 serine phosphorylation PubMed
nef HIV-1 Nef downregulates CD4 molecules from the cell surface of T, B, peripheral blood mononuclear and monocyte/macrophage cell lines as well as non-lymphoid cell lines PubMed
nef Overexpression of Nef-associated factor 1, Naf1, increases cell surface CD4 expression; HIV-1 Nef suppresses this activity of Naf1 to downregulate CD4 expression PubMed
Tat, p14 tat Expression of HRES-1/Rab4 is induced by HIV-1 tat, which in turn down-regulates expression of CD4 and susceptibility to re-infection by HIV-1 PubMed
tat CD4 and CD1a surface expression are greatly decreased in Tat expression Jurkat cells PubMed
tat HIV-1 Tat upregulates mRNA expression and cell surface levels of CD4 antigen in Jurkat cells PubMed
Vif, p23 vif Vif plays an important role in promoting HIV-1 binding to CD4 PubMed
Vpr, p15 vpr HIV-1 Nef-Vpr fusion proteins are efficiently incorporated into HIV-1 particles and possess CD4 downregulation activity in target cells PubMed
vpr HIV-1 Vpr increases expression of Nef protein from integrase-defective HIV-1. The Vpr-mediated expression of Nef from IN-minus HIV-1 results in CD4 downregulation PubMed
vpr HIV-1 Vpr downregulates the expression of surface CD4 receptors in Jurkat T cells PubMed
Vpu, p16 vpu Chimeras between the TMD of HIV-1 M Vpu and the cytoplasmic domains of SIVcpzPtt, SIVcpzPts, and SIVgor Vpu proteins are capable of binding to human CD4 PubMed
vpu A combination of molecular dynamics simulations and docking approaches shows the lowest energy structure of Vpu-CD4, indicating that the residues Leu-419 and Ile-416 in CD4 interact with the alanine rim (Ala-8/11/15/19) of Vpu PubMed
vpu Magic angle sample spinning NMR analysis confirms the correct insertion of the transmembrane domains from both HIV-1 Vpu and CD4 (residues 372-433) into the lipid bilayers PubMed
vpu The Val20 and Ser23 residues within the Vpu TMD are critical for Vpu-induced CD4 retention in the ER PubMed
vpu Mutation of the HIV-1 Vpu Trp22 does not prevent Vpu-CD4 interaction but enhances Vpu oligomerization. The CD4 Gly415 residue within the CD4 TMD is required for both Vpu-CD4 interaction and Vpu-induced CD4 degradation PubMed
vpu The HIV-1 Vpu Trp22 mutation in the Vpu transmembrane domain fails to induce CD4 degradation by reduced CD4 polyubiquitination. The Trp residue is highly conserved in all HIV-1 Vpu variants, including those of HIV-1 groups M, N, and O PubMed
vpu NMR analysis indicates that amino acids (residues 39-48 and 64-70) in both helices of the HIV-1 Vpu cytoplasmic region are important for its binding to CD4 PubMed
vpu Tetherin delGPI mutant directly interacts with HIV-1 Vpu and inhibits Vpu-induced degradation of tetherin and CD4 PubMed
vpu The putative cholesterol recognition amino acid consensus (CRAC) motif (residues 25-31) of HIV-1 Vpu mediates lipid raft association of Vpu and affects the downregulation of cell surface CD4 PubMed
vpu HIV-1 Vpu from subtype P can downregulate CD4 from cell surface PubMed
vpu Downregulation of CD4 and BST2 by HIV-1 Vpu is observed in HIV-1 infected humanized mice PubMed
vpu SCYL2 inhibits Vpu-induced BST2 and CD4 reduction at the cell surface by suppressing the phosphorylation of Vpu at positions Ser-52 and Ser-56 PubMed
vpu Poly-ubiquitination of the CD4 cytosolic tail by SCFbeta-TrCP is required for HIV-1 Vpu-induced CD4 degradation PubMed
vpu Co-expression of HIV-1 Vpu with beta-TrCP2 induces degradation of total cellular CD4 content; Vpu-mediated CD4 down-modulation is inhibited by double silencing of beta-TrCP1 and beta-TrCP2 PubMed
vpu The invariant leucine 63 and the valine 68 within the predicted second alpha-helical domain of the HIV-1 Vpu cytoplasmic tail are required for CD4 down-modulation. L63A and V68A mutants still bind CD4 and retain the ability to interact with beta-TrCP1 PubMed
vpu HIV-1 Vpu interacts with CD4 in living cells PubMed
vpu Replication-defective Vpu TM mutants (V9D and I19D) and cytoplasmic domain mutants (S56G and E59K) fail to downregulate cell surface CD4, suggesting that viral replication potential and ability to downregulate CD4 by Vpu are correlated PubMed
vpu HIV-1 Vpu Y35A/L39G mutant has a significant increase in CD4 surface expression compared to wild-type Vpu PubMed
vpu HIV-1 Vpu proteins from pandemic HIV-1 M strains, but not from nonpandemic HIV-1 N strains, degrade the viral receptor CD4 PubMed
vpu HIV-1 Vpu mediates retention of CD4 in the ER. Transmembrane domain interactions are the main determinant of ER retention of CD4 by Vpu PubMed
vpu The VCP-UFD1L-NPL4 complex is required for HIV-1 Vpu-induced CD4 degradation in the ER-associated degradation pathway. The ATPase activity of VCP and ubiquitin binding to UFD1L are important for CD4 degradation by Vpu PubMed
vpu A simian-human immunodeficiency virus (SHIVtm) with a scrambled amino acid sequence in the transmembrane domain of HIV-1 Vpu fails to downregulate cell surface expression of CD4 PubMed
vpu Downregulation of CD4 from the surface of HIV-1 infected cells by HIV-1 Vpu increases viral infectivity PubMed
vpu Cell surface CD4 inhibits HIV-1 particle release by interfering with Vpu activity, possibly by disrupting the oligomeric structure of Vpu PubMed
vpu HIV-1 Vpu mediated degradation of CD4 requires the function of proteasomes and results from the formation of a ternary complex between beta-TrCP, Vpu and CD4 which connects CD4 to the endoplasmic reticulum degradation pathway PubMed
vpu HIV-1 Vpu regulates the formation of intracellular HIV-1 gp160-CD4 complexes and liberates Golgi-targeted gp160 from CD4-dependent retention in the endoplasmic reticulum PubMed
vpu Phosphorylation of HIV-1 Vpu on two serine phosphoacceptor sites (amino acids 52 and 56) by casein kinase 2 is required for Vpu-mediated degradation of CD4 in the endoplasmic reticulum PubMed
vpu The C-terminal domain of HIV-1 Vpu (amino acids 76-81) interacts with the cytoplasmic domain of CD4 (amino acids 402-425) and causes the rapid degradation of CD4 in the endoplasmic reticulum PubMed

Go to the HIV-1, Human Protein Interaction Database

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    T cell receptor signaling pathway, organism-specific biosystemActivation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. En...
  • T cell receptor signaling pathway, conserved biosystem (from KEGG)
    T cell receptor signaling pathway, conserved biosystemActivation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. En...
  • TCR Signaling Pathway, organism-specific biosystem (from WikiPathways)
    TCR Signaling Pathway, organism-specific biosystemThe T-cell antigen receptor (TCR) complex is composed of a ligand-binding subunit, the ? and ? chains, and a signaling subunit, namely the CD3?, ? and ? chains and the TCR? chain. This complex partic...
  • TCR signaling, organism-specific biosystem (from REACTOME)
    TCR signaling, organism-specific biosystemThe TCR is a multisubunit complex that consists of clonotypic alpha/beta chains noncovalently associated with the invariant CD3 delta/epsilon/gamma and TCR zeta chains. T cell activation by antigen p...
  • TCR signaling in naive CD4+ T cells, organism-specific biosystem (from Pathway Interaction Database)
    TCR signaling in naive CD4+ T cells, organism-specific biosystem
    TCR signaling in naive CD4+ T cells
  • The role of Nef in HIV-1 replication and disease pathogenesis, organism-specific biosystem (from REACTOME)
    The role of Nef in HIV-1 replication and disease pathogenesis, organism-specific biosystemThe HIV-1 Nef protein is a 27-kDa myristoylated protein that is abundantly produced during the early phase of viral replication cycle. It is highly conserved in all primate lentiviruses, suggesting t...
  • Translocation of ZAP-70 to Immunological synapse, organism-specific biosystem (from REACTOME)
    Translocation of ZAP-70 to Immunological synapse, organism-specific biosystemThe dual phosphorylated ITAMs recruit Syk kinase ZAP-70 via their tandem SH2 domains (step 4). ZAP-70 subsequently undergoes phosphorylation on multiple tyrosine residues for further activation. ZAP-...
  • Vpu mediated degradation of CD4, organism-specific biosystem (from REACTOME)
    Vpu mediated degradation of CD4, organism-specific biosystemThe HIV-1 Vpu protein promotes the degradation of the CD4 receptor by recruiting an SCF like ubiquitination complex that promotes CD4 degradation. Vpu links beta-TrCP to CD4 at the ER membrane thro...
Products Interactant Other Gene Complex Source Pubs Description

Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
MHC class II protein binding NAS
Non-traceable Author Statement
more info
PubMed 
coreceptor activity NAS
Non-traceable Author Statement
more info
PubMed 
enzyme binding IPI
Inferred from Physical Interaction
more info
PubMed 
extracellular matrix structural constituent NAS
Non-traceable Author Statement
more info
PubMed 
glycoprotein binding IPI
Inferred from Physical Interaction
more info
PubMed 
protein binding IPI
Inferred from Physical Interaction
more info
PubMed 
protein homodimerization activity IDA
Inferred from Direct Assay
more info
PubMed 
protein kinase binding IPI
Inferred from Physical Interaction
more info
PubMed 
receptor activity TAS
Traceable Author Statement
more info
PubMed 
transmembrane signaling receptor activity TAS
Traceable Author Statement
more info
PubMed 
zinc ion binding IDA
Inferred from Direct Assay
more info
PubMed 
Process Evidence Code Pubs
T cell costimulation TAS
Traceable Author Statement
more info
 
T cell differentiation IDA
Inferred from Direct Assay
more info
PubMed 
T cell receptor signaling pathway TAS
Traceable Author Statement
more info
 
T cell selection IDA
Inferred from Direct Assay
more info
PubMed 
cell adhesion IEA
Inferred from Electronic Annotation
more info
 
cell surface receptor signaling pathway TAS
Traceable Author Statement
more info
PubMed 
cytokine production IEA
Inferred from Electronic Annotation
more info
 
defense response to Gram-negative bacterium IEA
Inferred from Electronic Annotation
more info
 
entry into host cell TAS
Traceable Author Statement
more info
 
enzyme linked receptor protein signaling pathway TAS
Traceable Author Statement
more info
PubMed 
immune response NAS
Non-traceable Author Statement
more info
PubMed 
induction by virus of host cell-cell fusion IDA
Inferred from Direct Assay
more info
PubMed 
innate immune response TAS
Traceable Author Statement
more info
 
maintenance of protein location in cell IDA
Inferred from Direct Assay
more info
PubMed 
positive regulation of calcium-mediated signaling IEA
Inferred from Electronic Annotation
more info
 
positive regulation of interleukin-2 biosynthetic process NAS
Non-traceable Author Statement
more info
PubMed 
positive regulation of peptidyl-tyrosine phosphorylation IEA
Inferred from Electronic Annotation
more info
 
positive regulation of protein kinase activity IDA
Inferred from Direct Assay
more info
PubMed 
protein palmitoleylation IDA
Inferred from Direct Assay
more info
PubMed 
regulation of T cell activation IDA
Inferred from Direct Assay
more info
PubMed 
regulation of defense response to virus by virus TAS
Traceable Author Statement
more info
 
signal transduction TAS
Traceable Author Statement
more info
PubMed 
transmembrane receptor protein tyrosine kinase signaling pathway NAS
Non-traceable Author Statement
more info
PubMed 
viral process TAS
Traceable Author Statement
more info
 
Component Evidence Code Pubs
T cell receptor complex NAS
Non-traceable Author Statement
more info
PubMed 
early endosome TAS
Traceable Author Statement
more info
 
endoplasmic reticulum lumen IEA
Inferred from Electronic Annotation
more info
 
endoplasmic reticulum membrane TAS
Traceable Author Statement
more info
 
external side of plasma membrane IDA
Inferred from Direct Assay
more info
PubMed 
integral component of membrane IEA
Inferred from Electronic Annotation
more info
 
membrane raft IEA
Inferred from Electronic Annotation
more info
 
plasma membrane IDA
Inferred from Direct Assay
more info
PubMed 
plasma membrane TAS
Traceable Author Statement
more info
 
Preferred Names
T-cell surface glycoprotein CD4
Names
T-cell surface glycoprotein CD4
CD4 receptor
CD4 antigen (p55)
T-cell surface antigen T4/Leu-3

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

  1. NG_027688.1 

    Range
    5001..36339
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_000616.4NP_000607.1  T-cell surface glycoprotein CD4 isoform 1 precursor

    See proteins identical to NP_000607.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) encodes the longest isoform (1) including a signal peptide and a mature peptide.
    Source sequence(s)
    AK316462, BC025782, CA305950, DA384217, U47924
    Consensus CDS
    CCDS8562.1
    UniProtKB/TrEMBL
    B4DT49
    UniProtKB/Swiss-Prot
    P01730
    Related
    ENSP00000011653, OTTHUMP00000238897, ENST00000011653, OTTHUMT00000399978
    Conserved Domains (6) summary
    cd07690
    Location:28121
    Blast Score: 457
    Ig1_CD4; First immunoglobulin (Ig) domain of CD4
    cd07694
    Location:123204
    Blast Score: 323
    Ig2_CD4; Second immunoglobulin (Ig) domain of CD4
    cd07695
    Location:209314
    Blast Score: 393
    Ig3_CD4_like; Third immunoglobulin (Ig) domain of CD4
    pfam12104
    Location:426453
    Blast Score: 150
    Tcell_CD4_Cterm; T cell CD4 receptor C terminal region
    smart00410
    Location:27122
    Blast Score: 141
    IG_like; Immunoglobulin like
    pfam05790
    Location:317389
    Blast Score: 171
    C2-set; Immunoglobulin C2-set domain
  2. NM_001195014.2NP_001181943.1  T-cell surface glycoprotein CD4 isoform 2

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) uses an alternate splice site, lacks two consecutive exons and initiates translation from an alternate start codon, compared to variant 1. The encoded isoform (2) is shorter and has a distinct N-terminus, compared to isoform 1.
    Source sequence(s)
    AK300052, AK315898, AK316462, BX378810, CA305950, DA384217, U47924
    UniProtKB/TrEMBL
    B0AZV7
    UniProtKB/TrEMBL
    B4DT49
    Conserved Domains (4) summary
    cd07695
    Location:30135
    Blast Score: 395
    Ig3_CD4_like; Third immunoglobulin (Ig) domain of CD4
    pfam12104
    Location:247274
    Blast Score: 151
    Tcell_CD4_Cterm; T cell CD4 receptor C terminal region
    cd12087
    Location:209249
    Blast Score: 78
    TM_EGFR-like; Transmembrane domain of the Epidermal Growth Factor Receptor family of Protein Tyrosine Kinases
    pfam05790
    Location:138210
    Blast Score: 174
    C2-set; Immunoglobulin C2-set domain
  3. NM_001195015.2NP_001181944.1  T-cell surface glycoprotein CD4 isoform 3

    See proteins identical to NP_001181944.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) uses an alternate splice site, lacks two consecutive exons and initiates translation from a downstream, in-frame start codon, compared to variant 1. Variants 3, 4 and 5 encode isoform 3, which has a shorter N-terminus, compared to isoform 1.
    Source sequence(s)
    AK300052, AK316462, BX378810, CA305950, DA384217
    UniProtKB/TrEMBL
    B4DT49
    Conserved Domains (4) summary
    pfam12104
    Location:153180
    Blast Score: 145
    Tcell_CD4_Cterm; T cell CD4 receptor C terminal region
    cd12087
    Location:115155
    Blast Score: 75
    TM_EGFR-like; Transmembrane domain of the Epidermal Growth Factor Receptor family of Protein Tyrosine Kinases
    pfam05790
    Location:44116
    Blast Score: 174
    C2-set; Immunoglobulin C2-set domain
    cl11960
    Location:143
    Blast Score: 205
    Ig; Immunoglobulin domain
  4. NM_001195016.2NP_001181945.1  T-cell surface glycoprotein CD4 isoform 3

    See proteins identical to NP_001181945.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (4) lacks two consecutive exons and initiates translation from a downstream, in-frame start codon, compared to variant 1. Variants 3, 4 and 5 encode isoform 3, which has a shorter N-terminus, compared to isoform 1.
    Source sequence(s)
    AK300052, AK316461, AK316462, BX378810, CA305950, DA384217
    UniProtKB/TrEMBL
    B4DT49
    Conserved Domains (4) summary
    pfam12104
    Location:153180
    Blast Score: 145
    Tcell_CD4_Cterm; T cell CD4 receptor C terminal region
    cd12087
    Location:115155
    Blast Score: 75
    TM_EGFR-like; Transmembrane domain of the Epidermal Growth Factor Receptor family of Protein Tyrosine Kinases
    pfam05790
    Location:44116
    Blast Score: 174
    C2-set; Immunoglobulin C2-set domain
    cl11960
    Location:143
    Blast Score: 205
    Ig; Immunoglobulin domain
  5. NM_001195017.2NP_001181946.1  T-cell surface glycoprotein CD4 isoform 3

    See proteins identical to NP_001181946.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (5) uses an alternate splice site, lacks two consecutive exons and initiates translation from a downstream, in-frame start codon, compared to variant 1. Variants 3, 4 and 5 encode isoform 3, which has a shorter N-terminus, compared to isoform 1.
    Source sequence(s)
    AK300052, AK316462, BX378810, CA305950, DA384217
    UniProtKB/TrEMBL
    B4DT49
    Conserved Domains (4) summary
    pfam12104
    Location:153180
    Blast Score: 145
    Tcell_CD4_Cterm; T cell CD4 receptor C terminal region
    cd12087
    Location:115155
    Blast Score: 75
    TM_EGFR-like; Transmembrane domain of the Epidermal Growth Factor Receptor family of Protein Tyrosine Kinases
    pfam05790
    Location:44116
    Blast Score: 174
    C2-set; Immunoglobulin C2-set domain
    cl11960
    Location:143
    Blast Score: 205
    Ig; Immunoglobulin domain

RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 106

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38 Primary Assembly

Genomic

  1. NC_000012.12 

    Range
    6789472..6820810
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

  1. AC_000144.1 

    Range
    6751975..6783457
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

Alternate CHM1_1.1

Genomic

  1. NC_018923.2 

    Range
    6897616..6928653
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

Suppressed Reference Sequence(s)

The following Reference Sequences have been suppressed. Explain

  1. NR_036545.1: Suppressed sequence

    Description
    NR_036545.1: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript.

Supplemental Content

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