CD4 is a single-pass type I cell-surface glycoprotein of the immunoglobulin superfamily, expressed on helper and regulatory T cells and, in human, also on monocytes, macrophages, dendritic cells and NK cells. Its ectodomain comprises four immunoglobulin-like domains, D1 to D4. The membrane-distal D1 domain binds a non-polymorphic concavity formed by the alpha-2 and beta-2 domains of MHC class II molecules, with Phe43 of CD4 inserting into that pocket; the interaction is of remarkably low affinity, so CD4 contributes not by independent ligation but by being co-recruited to a peptide-MHC class II complex that the T cell receptor is already engaging. On the cytoplasmic face, two cysteines in the short CD4 tail together with two cysteines in the LCK unique region coordinate a single Zn2+ ion in a zinc clasp, so that CD4 carries the Src-family kinase LCK and delivers it to the TCR-CD3 complex, where LCK phosphorylates the CD3 ITAMs and initiates the ZAP70-LAT-PLCG1 cascade. Palmitoylation of the membrane-proximal cysteines plus LCK association concentrate CD4 in plasma-membrane rafts and contribute to receptor and PKC-theta clustering at the immunological synapse, and D4-mediated dimerization is required for stable class II binding. CD4 thereby sets the sensitivity and the avidity threshold of class II-restricted recognition, which shapes thymic selection into the CD4 lineage and the subsequent helper T cell response, including IL-2 production. Outside T cells, MHC class II ligation of CD4 on human blood monocytes triggers MAPK- and Src-kinase-dependent differentiation into mature macrophages, a role absent in mouse monocytes, which do not express CD4. When the TCR and CD4 engage the same agonist peptide-MHC class II, their cytosolic juxtamembrane regions become proximal within a compact TCR-CD3-pMHCII-CD4 macrocomplex, and in resting T cells CD4 accumulates at microvillar tips in an LCK-dependent manner. A short CD4 isoform that retains D4, the transmembrane segment and the tail but lacks the distal domains still binds LCK yet cannot bind HLA class II. Loss-of-function variants cause an autosomal recessive CD4 deficiency (immunodeficiency 79) with recalcitrant HPV warts and, in a cohort of seven patients, no detectable CD4+ T cells but an expanded population of TCR alpha-beta CD4-CD8- double-negative cells with helper-like phenotypes that partly substitute for the missing compartment. CD4 is additionally the primary cellular receptor for HIV-1: the same D1 surface binds the envelope glycoprotein gp120 and triggers the conformational change that exposes the CCR5/CXCR4 site, and HIV-1 Nef and Vpu in turn down-regulate CD4 by clathrin-mediated endocytosis and ER-associated degradation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001618 virus receptor activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for virus receptor activity on the CD4 PAINT node, with human CD4 itself among the experimental sources. Reason: CD4 genuinely is the primary receptor for HIV-1: gp120 engages the same D1 surface that binds MHC class II, and CD4 binding triggers the conformational change that exposes the coreceptor site. This is a legitimate GO annotation but a non-physiological function exploited by a primate lentivirus, not part of the gene's own T cell biology, so it is kept as non-core. Supporting Evidence: PMID:9641677 The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. PMID:11535811 Human CD4 binds to HIV gp120 in a manner strikingly similar to the way in which CD4 interacts with pMHCII. file:human/CD4/CD4-uniprot.txt Primary receptor for human file:human/CD4/CD4-deep-research-falcon.md CD4 is therefore the initial cellular HIV receptor, whereas **CCR5/CXCR4 are the HIV entry coreceptors**. |
| GO:0001618 virus receptor activity | IDA PMID:9641677 Structure of an HIV gp120 envelope glycoprotein in complex w... | KEEP AS NON CORE | Summary: IDA from the gp120-CD4-17b crystal structure (PMID:9641677), which defines the CD4-binding site on gp120 and the CD4-induced coreceptor epitope. Reason: Direct structural and functional evidence that CD4 is the receptor mediating HIV-1 entry; a real activity, but viral and non-physiological, hence non-core. Supporting Evidence: PMID:9641677 The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. PMID:12089508 CD4, a member of the immunoglobulin superfamily of receptors that mediates cell-cell interactions in the immune system, is the primary receptor for HIV-1. PMID:10922058 Accumulating biochemical and structural evidence indicates that, in addition to contributing to viral attachment, CD4 triggers conformational alterations in the HIV envelope that promote recognition of the chemokine receptors and ultimately lead to membrane fusion file:human/CD4/CD4-deep-research-falcon.md CD4 is therefore the initial cellular HIV receptor, whereas **CCR5/CXCR4 are the HIV entry coreceptors**. |
| GO:0002684 positive regulation of immune system process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning IEA for the broad parent term positive regulation of immune system process. Reason: CD4 does positively influence immune responses, but at this level of generality the term adds nothing over the specific coreceptor and helper T cell terms the gene already carries; retained as a correct but uninformative parent. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0004888 transmembrane signaling receptor activity | TAS PMID:10358157 Inhibition of tyrosine kinase activation blocks the down-reg... | MODIFY | Summary: TAS for transmembrane signaling receptor activity, cited to a study of gp120-induced CXCR4 down-regulation in CD4+ T cells. Reason: CD4 has no intrinsic catalytic or signal-generating module: it signals only by delivering LCK to a primary receptor (the TCR-CD3 complex) or, when cross-linked, by LCK/MAPK activation. Coreceptor activity is the accurate molecular function. Proposed replacements: coreceptor activity Supporting Evidence: PMID:10358157 Thus, a CD4-associated signaling molecule(s) including p56lck is activated by gp120 and is required for the down-regulation of CXCR4. file:human/CD4/CD4-uniprot.txt In turn, recruits the Src kinase LCK to the vicinity of the |
| GO:0005102 signaling receptor binding | IBA GO_REF:0000033 | MODIFY | Summary: IBA for the broad parent signaling receptor binding, placed on the CD4 node with human and rat CD4 as sources. Reason: The binding partner the family is known for is the MHC class II molecule, a descendant term of signaling receptor binding; the specific term is both supported and more informative. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN008967719 SUPPORTS TRANSFER The node placement is sound -- MHC class II binding is ancestral in the CD4 family -- but the term asserted at the node is the generic parent rather than the specific ligand class. Proposed replacements: MHC class II protein binding Supporting Evidence: PMID:2823150 Thus, the CD4 protein, even in the absence of T-cell receptor-antigen interactions, can interact directly with class II antigens to function as a cell surface adhesion molecule. PMID:21900604 CD4 recognizes HLA-DR1 through its membrane-distal D1 domain, which contacts the membrane-proximal Ξ±2 and Ξ²2 domains of the MHC class II molecule |
| GO:0005102 signaling receptor binding | IEA GO_REF:0000107 | MODIFY | Summary: IEA transferred from rat CD4 (UniProtKB:P05540) by Ensembl Compara for signaling receptor binding. Reason: Orthology-based transfer is sound for CD4, but the informative term for the conserved interaction is MHC class II protein binding rather than the generic parent. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P05540 Β· Cd4 SUPPORTS TRANSFER Rat CD4 is a genuine ortholog; the defect is the generality of the transferred term, not the orthology. Proposed replacements: MHC class II protein binding Supporting Evidence: PMID:2823150 Thus, the CD4 protein, even in the absence of T-cell receptor-antigen interactions, can interact directly with class II antigens to function as a cell surface adhesion molecule. PMID:21900604 CD4 recognizes HLA-DR1 through its membrane-distal D1 domain, which contacts the membrane-proximal Ξ±2 and Ξ²2 domains of the MHC class II molecule |
| GO:0005201 extracellular matrix structural constituent | NAS PMID:12444132 CD4 dimers constitute the functional component required for ... | REMOVE | Summary: NAS for extracellular matrix structural constituent, cited to a study of CD4 dimers in T cell activation. Reason: CD4 is a single-pass type I plasma-membrane glycoprotein of the immunoglobulin superfamily and is not a structural component of the extracellular matrix; the cited paper reports D4-mediated dimerization required for coreceptor function, not matrix structure. Supporting Evidence: PMID:12444132 More importantly, we demonstrate that dimer formation is essential for the coligand and coreceptor functions of CD4 in T cell activation. PMID:2990730 The deduced protein sequence reveals that T4 is an integral membrane protein that shares significant amino acid and structural homologies with members of the immunoglobulin supergene family. |
| GO:0005515 protein binding | IPI PMID:10816381 Interactions of CCR5 and CXCR4 with CD4 and gp120 in human b... | REMOVE | Summary: Generic protein binding IPI recording co-immunoprecipitation of CD4 with the chemokine receptor CCR5 in the context of HIV-1 entry. Reason: Generic protein binding carries no functional information, so the row is removed per the repository's curation policy; removal does not question the reported interaction. CD4 and CCR5 act sequentially on gp120 during entry, which is already captured by virus receptor activity and symbiont entry into host cell; the association itself supports no specific molecular function for CD4. Supporting Evidence: PMID:10816381 In addition, DC behaved similarly to macrophages, lymphocytes, and monocytes in their ability to support formation of complexes between CD4 and the other major HIV-1 coreceptor CCR5 even in the absence of gp120 as demonstrated by CD4 coimmunoprecipitation with anti-CCR5 antibodies. |
| GO:0005515 protein binding | IPI PMID:10922058 Energetics of the HIV gp120-CD4 binding reaction. | MODIFY | Summary: Generic protein binding IPI recording a structural or thermodynamic study of the CD4-HIV-1 gp120 envelope interaction. Reason: The interaction is with the HIV-1 envelope glycoprotein and the informative molecular function is virus receptor activity: CD4 binds gp120 and induces the conformational change that creates the coreceptor-binding site. Bare protein binding should be replaced by that term. Proposed replacements: virus receptor activity Supporting Evidence: PMID:10922058 Accumulating biochemical and structural evidence indicates that, in addition to contributing to viral attachment, CD4 triggers conformational alterations in the HIV envelope that promote recognition of the chemokine receptors and ultimately lead to membrane fusion PMID:9641677 The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. |
| GO:0005515 protein binding | IPI PMID:11113139 Cloning of ACP33 as a novel intracellular ligand of CD4. | REMOVE | Summary: Generic protein binding IPI for the yeast two-hybrid partner ACP33/SPG21 (maspardin), which binds the CD4 C-terminal hydrophobic residues. Reason: Generic protein binding carries no functional information, so the row is removed per the repository's curation policy; removal does not question the reported interaction. The reported role is negative modulation of CD4 costimulation, which is a property of the partner rather than a molecular function of CD4. Supporting Evidence: PMID:11113139 A two-hybrid screen with the intracellular portion of CD4 identified a previously unknown 33-kDa protein, ACP33 (acidic cluster protein 33), as a novel intracellular binding partner of CD4. |
| GO:0005515 protein binding | IPI PMID:11264384 Direct in vitro binding of full-length human immunodeficienc... | REMOVE | Summary: Generic protein binding IPI recording the interaction of CD4's cytoplasmic tail with HIV-1 Nef. Reason: Generic protein binding carries no functional information, so the row is removed per the repository's curation policy; removal does not question the reported interaction. Here CD4 is the host protein that a viral accessory protein hijacks for down-regulation; by the convention that immune-evasion activity is annotated on the viral protein, the host protein gains no molecular function from being targeted. Supporting Evidence: PMID:11264384 All these data suggest that the existence of a preformed Ξ±-helix in CD4 supports binding to Nef. |
| GO:0005515 protein binding | IPI PMID:15660419 Constitutive association of cell surface CCR5 and CXCR4 in t... | REMOVE | Summary: Generic protein binding IPI recording co-immunoprecipitation of CD4 with the chemokine receptor CCR5 in the context of HIV-1 entry. Reason: Generic protein binding carries no functional information, so the row is removed per the repository's curation policy; removal does not question the reported interaction. CD4 and CCR5 act sequentially on gp120 during entry, which is already captured by virus receptor activity and symbiont entry into host cell; the association itself supports no specific molecular function for CD4. Supporting Evidence: PMID:15660419 In CD4 expressing CCR5 and CXCR4 double positive NIH 3T3 cells, immunoprecipitation followed by Western blot analysis revealed that CCR5 was associated with CXCR4 and CD4. |
| GO:0005515 protein binding | IPI PMID:16888650 Glucocorticoids cause rapid dissociation of a T-cell-recepto... | REMOVE | Summary: Generic protein binding IPI pairing CD4 with the glucocorticoid receptor (NR3C1) from a TCR-associated multiprotein complex study. Reason: Generic protein binding carries no functional information, so the row is removed per the repository's curation policy; removal does not question the reported interaction. The complex is held together through LCK/FYN and HSP90; a direct CD4-GR molecular function is not supported. Supporting Evidence: PMID:16888650 The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation. |
| GO:0005515 protein binding | IPI PMID:16888650 Glucocorticoids cause rapid dissociation of a T-cell-recepto... | MODIFY | Summary: Generic protein binding IPI from a study in which the glucocorticoid receptor, HSP90, LCK and FYN are found in a TCR-linked multiprotein complex; the CD4 row records the CD4-LCK pairing. Reason: CD4's functionally important partner here is the tyrosine kinase LCK, bound through the zinc-clasp motif of the cytoplasmic tail; protein tyrosine kinase binding states that, whereas protein binding does not. Proposed replacements: protein tyrosine kinase binding Supporting Evidence: PMID:16888650 LCK predominantly associates with CD4 or CD8 cell-surface receptors and FYN binds to CD3 co-receptors, resulting in LCK and FYN kinase activation. PMID:14500983 The T cell coreceptors CD4 and CD8 both associate via their cytoplasmic tails with the N-terminus of the Src-family tyrosine kinase Lck. |
| GO:0005515 protein binding | IPI PMID:17005671 Growth transformation of human T cells by herpesvirus saimir... | MODIFY | Summary: Generic protein binding IPI from a herpesvirus saimiri Tip study, recording a CD4-LCK interaction alongside Tip-LCK binding. Reason: Again the partner is LCK, so protein tyrosine kinase binding is the informative replacement for the bare term. Proposed replacements: protein tyrosine kinase binding Supporting Evidence: PMID:17005671 The major interaction partner of Tip is the protein tyrosine kinase Lck, a key regulator of T-cell activation. PMID:3262426 Our data demonstrate that p56lck is specifically modulated with either CD4 or CD8 following antibody-mediated cross-linking of these molecules and that a large fraction of the total cellular lck protein can be coimmunoprecipitated with these surface glycoproteins. |
| GO:0005515 protein binding | IPI PMID:17301785 Structural definition of a conserved neutralization epitope ... | MODIFY | Summary: Generic protein binding IPI recording a structural or thermodynamic study of the CD4-HIV-1 gp120 envelope interaction. Reason: The interaction is with the HIV-1 envelope glycoprotein and the informative molecular function is virus receptor activity: CD4 binds gp120 and induces the conformational change that creates the coreceptor-binding site. Bare protein binding should be replaced by that term. Proposed replacements: virus receptor activity Supporting Evidence: PMID:17301785 A highly coordinated rearrangement of the inner domain allows for formation of the bridging sheet, which welds CD4 into place. PMID:9641677 The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. |
| GO:0005515 protein binding | IPI PMID:19333378 The phospholipid scramblases 1 and 4 are cellular receptors ... | REMOVE | Summary: Generic protein binding IPI for phospholipid scramblase 4 (PLSCR4), reported to interact with CD4 at the plasma membrane. Reason: Generic protein binding carries no functional information, so the row is removed per the repository's curation policy; removal does not question the reported interaction. The paper's functional claim is that SLPI acts through the scramblases; no specific CD4 activity follows. Supporting Evidence: PMID:19333378 At the molecular level, we show that SLPI is a ligand for both PLSCR1 and PLSCR4, and we reveal that PLSCR1 and PLSCR4 interact directly with the CD4 receptor at the cell surface of T lymphocytes. |
| GO:0005515 protein binding | IPI PMID:20080564 Structure of HIV-1 gp120 with gp41-interactive region reveal... | MODIFY | Summary: Generic protein binding IPI recording a structural or thermodynamic study of the CD4-HIV-1 gp120 envelope interaction. Reason: The interaction is with the HIV-1 envelope glycoprotein and the informative molecular function is virus receptor activity: CD4 binds gp120 and induces the conformational change that creates the coreceptor-binding site. Bare protein binding should be replaced by that term. Proposed replacements: virus receptor activity Supporting Evidence: PMID:20080564 Binding of the initial receptor, CD4, induces changes in gp120 conformation that allow high-affinity interaction with the coreceptor, CCR5 or CXCR4, and the formation of a gp41 prehairpin intermediate. PMID:9641677 The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. |
| GO:0005515 protein binding | IPI PMID:20357769 Structure of a clade C HIV-1 gp120 bound to CD4 and CD4-indu... | MODIFY | Summary: Generic protein binding IPI recording a structural or thermodynamic study of the CD4-HIV-1 gp120 envelope interaction. Reason: The interaction is with the HIV-1 envelope glycoprotein and the informative molecular function is virus receptor activity: CD4 binds gp120 and induces the conformational change that creates the coreceptor-binding site. Bare protein binding should be replaced by that term. Proposed replacements: virus receptor activity Supporting Evidence: PMID:20357769 The structure, a complex between gp120, the host receptor CD4 and the CD4-induced antibody 21c, reveals that the 21c epitope involves contacts with gp120, a nonself antigen, and with CD4, an autoantigen. PMID:9641677 The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. |
| GO:0005515 protein binding | IPI PMID:23890821 Deubiquitinases sharpen substrate discrimination during memb... | REMOVE | Summary: Generic protein binding IPI recording the interaction of CD4's cytoplasmic tail with HIV-1 Vpu. Reason: Generic protein binding carries no functional information, so the row is removed per the repository's curation policy; removal does not question the reported interaction. Here CD4 is the host protein that a viral accessory protein hijacks for down-regulation; by the convention that immune-evasion activity is annotated on the viral protein, the host protein gains no molecular function from being targeted. Supporting Evidence: PMID:23890821 As expected, mCD4 ubiquitination in the radiolabeled recombinant system displayed a strict dependence on phospho-Vpu, showed high processivity and was easily quantifiable given that only the substrate was radiolabeled |
| GO:0005515 protein binding | IPI PMID:26098315 Crystal structure, conformational fixation and entry-related... | MODIFY | Summary: Generic protein binding IPI recording a structural or thermodynamic study of the CD4-HIV-1 gp120 envelope interaction. Reason: The interaction is with the HIV-1 envelope glycoprotein and the informative molecular function is virus receptor activity: CD4 binds gp120 and induces the conformational change that creates the coreceptor-binding site. Bare protein binding should be replaced by that term. Proposed replacements: virus receptor activity Supporting Evidence: PMID:26098315 recognition by one CD4 without the previously recognized antigenic hallmarks of CD4 binding such as bridging sheet formation; and second, recognition by more than one CD4 along with exposure or formation of characteristic CD4-induced epitopes PMID:9641677 The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. |
| GO:0005515 protein binding | IPI PMID:27114505 Remarkably low affinity of CD4/peptide-major histocompatibil... | MODIFY | Summary: Generic protein binding IPI for the CD4 interaction with the class II molecule HLA-DR (HLA-DRA), measured as the weakest cell-cell recognition interaction reported. Reason: The partner is an MHC class II protein complex, so the informative term is MHC class II protein complex binding; the same paper already supports that term as an IDA row. Proposed replacements: MHC class II protein complex binding Supporting Evidence: PMID:27114505 to measure the 2D K d for the CD4/pMHC II interaction, which proves to the best of our knowledge to be the weakest such interaction ever studied PMID:21900604 CD4 recognizes HLA-DR1 through its membrane-distal D1 domain, which contacts the membrane-proximal Ξ±2 and Ξ²2 domains of the MHC class II molecule |
| GO:0005515 protein binding | IPI PMID:27114505 Remarkably low affinity of CD4/peptide-major histocompatibil... | MODIFY | Summary: Generic protein binding IPI for the CD4 interaction with the class II molecule HLA-DR (HLA-DRB1), measured as the weakest cell-cell recognition interaction reported. Reason: The partner is an MHC class II protein complex, so the informative term is MHC class II protein complex binding; the same paper already supports that term as an IDA row. Proposed replacements: MHC class II protein complex binding Supporting Evidence: PMID:27114505 to measure the 2D K d for the CD4/pMHC II interaction, which proves to the best of our knowledge to be the weakest such interaction ever studied PMID:21900604 CD4 recognizes HLA-DR1 through its membrane-distal D1 domain, which contacts the membrane-proximal Ξ±2 and Ξ²2 domains of the MHC class II molecule |
| GO:0005515 protein binding | IPI PMID:30542158 Structural basis of coreceptor recognition by HIV-1 envelope... | REMOVE | Summary: Generic protein binding IPI recording co-immunoprecipitation of CD4 with the chemokine receptor CCR5 in the context of HIV-1 entry. Reason: Generic protein binding carries no functional information, so the row is removed per the repository's curation policy; removal does not question the reported interaction. CD4 and CCR5 act sequentially on gp120 during entry, which is already captured by virus receptor activity and symbiont entry into host cell; the association itself supports no specific molecular function for CD4. Supporting Evidence: PMID:30542158 Flow cytometry histograms of HIV-1 gp120 binding to CCR5 expressed on the cell surfaces in the absence (orange) or presence (red) of soluble CD4 |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Generic protein binding IPI for LAMP2, a hit from a large yeast two-hybrid neurodegenerative-disease interactome screen. Reason: Generic protein binding carries no functional information, so the row is removed per the repository's curation policy; removal does not question the reported interaction. A single large-scale two-hybrid hit with no CD4-directed follow-up gives no functional information about CD4. Supporting Evidence: PMID:32814053 This network reveals interconnectivity across diseases and links many known ND-causing proteins |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Generic protein binding IPI for SH3GLB1, a hit from a large yeast two-hybrid neurodegenerative-disease interactome screen. Reason: Generic protein binding carries no functional information, so the row is removed per the repository's curation policy; removal does not question the reported interaction. A single large-scale two-hybrid hit with no CD4-directed follow-up gives no functional information about CD4. Supporting Evidence: PMID:32814053 This network reveals interconnectivity across diseases and links many known ND-causing proteins |
| GO:0005515 protein binding | IPI PMID:7831289 Human immunodeficiency virus type 1 Nef and p56lck protein-t... | REMOVE | Summary: Generic protein binding IPI recording the interaction of CD4's cytoplasmic tail with HIV-1 Nef. Reason: Generic protein binding carries no functional information, so the row is removed per the repository's curation policy; removal does not question the reported interaction. Here CD4 is the host protein that a viral accessory protein hijacks for down-regulation; by the convention that immune-evasion activity is annotated on the viral protein, the host protein gains no molecular function from being targeted. Supporting Evidence: PMID:7831289 Mutations in CD4 that prevent down-modulation by Nef also decrease CD4 association with p56lck and prevent Nef-induced disruption of CD4-p56lck complexes. |
| GO:0005515 protein binding | IPI PMID:9168119 Dimeric association and segmental variability in the structu... | REMOVE | Summary: Generic protein binding IPI listing CD81 as a CD4 partner, cited to the soluble CD4 crystal structure paper. Reason: Generic protein binding carries no functional information, so the row is removed per the repository's curation policy; removal does not question the reported interaction. The cited structural study characterises CD4 D4-mediated homodimerization rather than a CD4-CD81 function, so no specific replacement term is supportable. Supporting Evidence: PMID:9168119 These structures have a hinge-like variability at the D1D2 to D3D4 junction that might be important in immune recognition and HIV fusion, and a common dimeric association through D4 domains. |
| GO:0005769 early endosome | TAS Reactome:R-HSA-167597 | KEEP AS NON CORE | Summary: TAS from Reactome reactions describing internalization and lysosomal degradation of CD4 in the HIV-1 Nef pathway, placing CD4 in the early endosome. Reason: CD4 does reach the endosomal system, both through constitutive PKC-dependent internalization and, much more prominently, when HIV-1 Nef recruits AP-2 to the dileucine motif of its tail and routes it to lysosomes. The location is real but is a consequence of trafficking and viral down-regulation rather than where CD4 does its work. Supporting Evidence: PMID:8124721 Here, we demonstrate that Nef acts by inducing CD4 endocytosis, resulting in its degradation in lysosomes. PMID:8124721 Within this region, a dileucine motif, reminiscent of an endocytosis and lysosomal targeting signal found in the CD3 gamma and delta chains, is crucial for CD4 response to Nef. file:human/CD4/CD4-uniprot.txt 1 Nef protein that increases clathrin-dependent endocytosis of this file:human/CD4/CD4-deep-research-falcon.md In primary macrophages, which lack the lymphocyte-associated LCK examined in one study, CD4 recycles constitutively and approximately **40β50% was intracellular at steady state**, versus approximately **90% surface localization in the lymphoid-cell comparison**. file:human/CD4/CD4-deep-research-falcon.md In primary macrophages, which lack the lymphocyte-associated LCK examined in one study, CD4 recycles constitutively and approximately **40β50% was intracellular at steady state**, versus approximately **90% surface localization in the lymphoid-cell comparison**. file:human/CD4/CD4-deep-research-falcon.md In primary macrophages, which lack the lymphocyte-associated LCK examined in one study, CD4 recycles constitutively and approximately **40β50% was intracellular at steady state**, versus approximately **90% surface localization in the lymphoid-cell comparison**. |
| GO:0005769 early endosome | TAS Reactome:R-HSA-167601 | KEEP AS NON CORE | Summary: TAS from Reactome reactions describing internalization and lysosomal degradation of CD4 in the HIV-1 Nef pathway, placing CD4 in the early endosome. Reason: CD4 does reach the endosomal system, both through constitutive PKC-dependent internalization and, much more prominently, when HIV-1 Nef recruits AP-2 to the dileucine motif of its tail and routes it to lysosomes. The location is real but is a consequence of trafficking and viral down-regulation rather than where CD4 does its work. Supporting Evidence: PMID:8124721 Here, we demonstrate that Nef acts by inducing CD4 endocytosis, resulting in its degradation in lysosomes. PMID:8124721 Within this region, a dileucine motif, reminiscent of an endocytosis and lysosomal targeting signal found in the CD3 gamma and delta chains, is crucial for CD4 response to Nef. file:human/CD4/CD4-uniprot.txt 1 Nef protein that increases clathrin-dependent endocytosis of this file:human/CD4/CD4-deep-research-falcon.md In primary macrophages, which lack the lymphocyte-associated LCK examined in one study, CD4 recycles constitutively and approximately **40β50% was intracellular at steady state**, versus approximately **90% surface localization in the lymphoid-cell comparison**. file:human/CD4/CD4-deep-research-falcon.md In primary macrophages, which lack the lymphocyte-associated LCK examined in one study, CD4 recycles constitutively and approximately **40β50% was intracellular at steady state**, versus approximately **90% surface localization in the lymphoid-cell comparison**. file:human/CD4/CD4-deep-research-falcon.md In primary macrophages, which lack the lymphocyte-associated LCK examined in one study, CD4 recycles constitutively and approximately **40β50% was intracellular at steady state**, versus approximately **90% surface localization in the lymphoid-cell comparison**. |
| GO:0005769 early endosome | TAS Reactome:R-HSA-200879 | KEEP AS NON CORE | Summary: TAS from Reactome reactions describing internalization and lysosomal degradation of CD4 in the HIV-1 Nef pathway, placing CD4 in the early endosome. Reason: CD4 does reach the endosomal system, both through constitutive PKC-dependent internalization and, much more prominently, when HIV-1 Nef recruits AP-2 to the dileucine motif of its tail and routes it to lysosomes. The location is real but is a consequence of trafficking and viral down-regulation rather than where CD4 does its work. Supporting Evidence: PMID:8124721 Here, we demonstrate that Nef acts by inducing CD4 endocytosis, resulting in its degradation in lysosomes. PMID:8124721 Within this region, a dileucine motif, reminiscent of an endocytosis and lysosomal targeting signal found in the CD3 gamma and delta chains, is crucial for CD4 response to Nef. file:human/CD4/CD4-uniprot.txt 1 Nef protein that increases clathrin-dependent endocytosis of this file:human/CD4/CD4-deep-research-falcon.md In primary macrophages, which lack the lymphocyte-associated LCK examined in one study, CD4 recycles constitutively and approximately **40β50% was intracellular at steady state**, versus approximately **90% surface localization in the lymphoid-cell comparison**. file:human/CD4/CD4-deep-research-falcon.md In primary macrophages, which lack the lymphocyte-associated LCK examined in one study, CD4 recycles constitutively and approximately **40β50% was intracellular at steady state**, versus approximately **90% surface localization in the lymphoid-cell comparison**. file:human/CD4/CD4-deep-research-falcon.md In primary macrophages, which lack the lymphocyte-associated LCK examined in one study, CD4 recycles constitutively and approximately **40β50% was intracellular at steady state**, versus approximately **90% surface localization in the lymphoid-cell comparison**. |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000107 | REMOVE | Summary: IEA for endoplasmic reticulum lumen, transferred from rat CD4 by Ensembl Compara. Reason: CD4 is a single-pass type I membrane protein: during biosynthesis, and when HIV-1 gp160 sequesters it, the protein sits in the ER membrane with its ectodomain facing the lumen, but it is never a soluble lumenal protein. The co-annotated ER membrane rows capture this correctly. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:P05540 Β· Cd4 SUPPORTS SOURCE BUT NOT TARGET Whatever the rat donor row intends, a lumenal location is wrong for a type I membrane protein in either species. Supporting Evidence: PMID:2990730 The deduced protein sequence reveals that T4 is an integral membrane protein that shares significant amino acid and structural homologies with members of the immunoglobulin supergene family. file:human/CD4/CD4-uniprot.txt is also down-modulated by HIV-1 Envelope polyprotein gp160 that |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA for endoplasmic reticulum membrane, transferred from rat CD4. Reason: Newly synthesised CD4 is inserted into the ER membrane, and HIV-1 gp160 and Vpu both act on CD4 there; this is a biosynthetic and virus-induced location rather than a site of function. Supporting Evidence: file:human/CD4/CD4-uniprot.txt is also down-modulated by HIV-1 Envelope polyprotein gp160 that |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-180573 | KEEP AS NON CORE | Summary: TAS from Reactome reactions describing HIV-1 Vpu-mediated ubiquitination and ERAD of CD4, which take place at the ER membrane. Reason: The ER membrane localization is correct for both normal biosynthesis and the Vpu-driven degradation pathway, but CD4 carries out its coreceptor function at the cell surface. Supporting Evidence: PMID:23890821 As expected, mCD4 ubiquitination in the radiolabeled recombinant system displayed a strict dependence on phospho-Vpu, showed high processivity and was easily quantifiable given that only the substrate was radiolabeled file:human/CD4/CD4-uniprot.txt is also down-modulated by HIV-1 Envelope polyprotein gp160 that |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-180591 | KEEP AS NON CORE | Summary: TAS from Reactome reactions describing HIV-1 Vpu-mediated ubiquitination and ERAD of CD4, which take place at the ER membrane. Reason: The ER membrane localization is correct for both normal biosynthesis and the Vpu-driven degradation pathway, but CD4 carries out its coreceptor function at the cell surface. Supporting Evidence: PMID:23890821 As expected, mCD4 ubiquitination in the radiolabeled recombinant system displayed a strict dependence on phospho-Vpu, showed high processivity and was easily quantifiable given that only the substrate was radiolabeled file:human/CD4/CD4-uniprot.txt is also down-modulated by HIV-1 Envelope polyprotein gp160 that |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-180597 | KEEP AS NON CORE | Summary: TAS from Reactome reactions describing HIV-1 Vpu-mediated ubiquitination and ERAD of CD4, which take place at the ER membrane. Reason: The ER membrane localization is correct for both normal biosynthesis and the Vpu-driven degradation pathway, but CD4 carries out its coreceptor function at the cell surface. Supporting Evidence: PMID:23890821 As expected, mCD4 ubiquitination in the radiolabeled recombinant system displayed a strict dependence on phospho-Vpu, showed high processivity and was easily quantifiable given that only the substrate was radiolabeled file:human/CD4/CD4-uniprot.txt is also down-modulated by HIV-1 Envelope polyprotein gp160 that |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-180599 | KEEP AS NON CORE | Summary: TAS from Reactome reactions describing HIV-1 Vpu-mediated ubiquitination and ERAD of CD4, which take place at the ER membrane. Reason: The ER membrane localization is correct for both normal biosynthesis and the Vpu-driven degradation pathway, but CD4 carries out its coreceptor function at the cell surface. Supporting Evidence: PMID:23890821 As expected, mCD4 ubiquitination in the radiolabeled recombinant system displayed a strict dependence on phospho-Vpu, showed high processivity and was easily quantifiable given that only the substrate was radiolabeled file:human/CD4/CD4-uniprot.txt is also down-modulated by HIV-1 Envelope polyprotein gp160 that |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-180606 | KEEP AS NON CORE | Summary: TAS from Reactome reactions describing HIV-1 Vpu-mediated ubiquitination and ERAD of CD4, which take place at the ER membrane. Reason: The ER membrane localization is correct for both normal biosynthesis and the Vpu-driven degradation pathway, but CD4 carries out its coreceptor function at the cell surface. Supporting Evidence: PMID:23890821 As expected, mCD4 ubiquitination in the radiolabeled recombinant system displayed a strict dependence on phospho-Vpu, showed high processivity and was easily quantifiable given that only the substrate was radiolabeled file:human/CD4/CD4-uniprot.txt is also down-modulated by HIV-1 Envelope polyprotein gp160 that |
| GO:0005886 plasma membrane | EXP PMID:12089508 Disulfide exchange in domain 2 of CD4 is required for entry ... | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | EXP PMID:12517957 Lipid raft distribution of CD4 depends on its palmitoylation... | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | EXP PMID:2990730 The isolation and nucleotide sequence of a cDNA encoding the... | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | IDA PMID:11390434 The transmembrane adaptor protein TRIM regulates T cell rece... | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | IDA PMID:19333378 The phospholipid scramblases 1 and 4 are cellular receptors ... | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | IDA PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage di... | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | IDA PMID:2823150 Interaction between CD4 and class II MHC molecules mediates ... | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | IDA PMID:8124721 Nef induces CD4 endocytosis: requirement for a critical dile... | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1471314 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164500 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164507 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164508 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164509 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164510 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164515 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164521 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164524 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-167537 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-167566 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-167597 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-200879 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202165 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202168 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202174 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202214 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202216 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202233 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202245 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202248 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202291 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202307 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202344 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-389758 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-449087 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8852200 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8855381 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8866277 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867754 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867756 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868071 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868072 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868230 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868236 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868648 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868651 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868661 | ACCEPT | Summary: Plasma membrane localization of CD4, supported by many independent experimental and pathway-database sources, including imaging and biochemistry in T cells and monocytes and Reactome reactions for TCR signaling, HIV-1 entry and CD4 down-regulation. Reason: The plasma membrane is where CD4 functions: it is a single-pass type I cell-surface glycoprotein that engages peptide-MHC class II on the opposing cell and recruits LCK on the cytoplasmic face. Supporting Evidence: PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0006955 immune response | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: IEA from the InterPro CD4 signature for the broad term immune response. Reason: True but far too general to be a core statement; the specific T cell receptor signaling and helper T cell terms carry the information. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0006955 immune response | NAS PMID:8512039 Role of CD4 and CD8 in T cell activation and differentiation... | KEEP AS NON CORE | Summary: NAS for immune response from a review of CD4 and CD8 in T cell activation. Reason: Correct at a very general level only. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0007155 cell adhesion | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: IEA from InterPro for cell adhesion. Reason: CD4-class II binding does mediate adhesion between a T cell and an antigen-presenting cell, as the founding experiment showed, but the affinity is extremely low and the physiological role is coreceptor function rather than adhesion per se; kept as a real but peripheral process. Supporting Evidence: PMID:2823150 Thus, the CD4 protein, even in the absence of T-cell receptor-antigen interactions, can interact directly with class II antigens to function as a cell surface adhesion molecule. PMID:27114505 to measure the 2D K d for the CD4/pMHC II interaction, which proves to the best of our knowledge to be the weakest such interaction ever studied |
| GO:0007165 signal transduction | TAS PMID:10358157 Inhibition of tyrosine kinase activation blocks the down-reg... | MODIFY | Summary: TAS for the broad term signal transduction, cited to a study of gp120-triggered, LCK-dependent CXCR4 down-regulation in CD4+ T cells. Reason: CD4-initiated signaling is LCK-dependent signaling at an antigen receptor; the T cell receptor signaling pathway is the specific process CD4 contributes to and is already supported by an independent IDA row. Proposed replacements: T cell receptor signaling pathway Supporting Evidence: PMID:10358157 Thus, a CD4-associated signaling molecule(s) including p56lck is activated by gp120 and is required for the down-regulation of CXCR4. file:human/CD4/CD4-uniprot.txt In turn, recruits the Src kinase LCK to the vicinity of the |
| GO:0007165 signal transduction | TAS PMID:9558100 Dendritic cells express multiple chemokine receptors used as... | MODIFY | Summary: TAS for signal transduction, cited to a study of chemokine receptors on dendritic cells serving as HIV entry coreceptors. Reason: The cited reference is about HIV-1 entry rather than CD4-initiated signal transduction; symbiont entry into host cell is the process the reference actually bears on, and CD4 performs the receptor step of it. Proposed replacements: symbiont entry into host cell Supporting Evidence: PMID:9558100 In this study, we have identified the presence of multiple chemokine receptors on dendritic cells (DC) that may function as coreceptors for HIV entry. PMID:9641677 The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. |
| GO:0007166 cell surface receptor signaling pathway | TAS PMID:9780207 HIV-1 envelope gp120 inhibits the monocyte response to chemo... | KEEP AS NON CORE | Summary: TAS for the parent term cell surface receptor signaling pathway, cited to a study in which gp120 ligation of CD4 down-regulates monocyte chemokine receptors, an effect requiring the CD4 cytoplasmic tail. Reason: The reference does show tail-dependent CD4 signaling, so the general term is not wrong; it is simply uninformative next to the T cell receptor signaling pathway annotation. Supporting Evidence: PMID:9780207 This broad inhibition of monocyte activation by chemoattractants required interaction of gp120 with CD4, since the effect of gp120 was only observed in CD4+ monocytes and in HEK 293 cells only if cotransfected with both chemokine receptors and an intact CD4, but not a CD4 lacking its cytoplasmic domain. |
| GO:0007167 enzyme-linked receptor protein signaling pathway | TAS PMID:10358157 Inhibition of tyrosine kinase activation blocks the down-reg... | MODIFY | Summary: TAS for enzyme-linked receptor protein signaling pathway, cited to the gp120/CXCR4 study. Reason: CD4 is not an enzyme-linked receptor; it has no catalytic domain and signals only by delivering the Src-family kinase LCK to the TCR-CD3 complex. The T cell receptor signaling pathway is the accurate process. Proposed replacements: T cell receptor signaling pathway Supporting Evidence: file:human/CD4/CD4-uniprot.txt In turn, recruits the Src kinase LCK to the vicinity of the PMID:10358157 Thus, a CD4-associated signaling molecule(s) including p56lck is activated by gp120 and is required for the down-regulation of CXCR4. |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | NAS PMID:8512039 Role of CD4 and CD8 in T cell activation and differentiation... | KEEP AS NON CORE | Summary: NAS for cell surface receptor protein tyrosine kinase signaling pathway from a review of CD4/CD8 function. Reason: Defensible in that CD4-bound LCK is the tyrosine kinase that initiates the cascade, but the receptor concerned is the TCR; retained as a non-core, less apt framing of the same biology. Supporting Evidence: PMID:14500983 The T cell coreceptors CD4 and CD8 both associate via their cytoplasmic tails with the N-terminus of the Src-family tyrosine kinase Lck. file:human/CD4/CD4-uniprot.txt In turn, recruits the Src kinase LCK to the vicinity of the |
| GO:0008270 zinc ion binding | IDA PMID:9668045 A Zn2+ ion links the cytoplasmic tail of CD4 and the N-termi... | ACCEPT | Summary: IDA for zinc ion binding, from the demonstration that the CD4 cytoplasmic tail and the LCK N-terminal region jointly coordinate a single Zn2+ ion. Reason: This is a genuine, structurally defined metal-binding activity of CD4: two tail cysteines together with two LCK cysteines form the zinc clasp that tethers the kinase to the coreceptor, and the complex dissociates on chelation. Supporting Evidence: PMID:9668045 These results are consistent with the proposal that Lck and CD4 associate by thiol-mediated co-coordination of zinc. PMID:9668045 Biochemical and biophysical experiments show that the complex dissociates in the presence of EDTA and that it contains a single Zn2+ ion. PMID:14500983 The coreceptor tails and the Lck N-terminus are unstructured in isolation but assemble in the presence of zinc to form compactly folded heterodimeric domains. |
| GO:0008289 lipid binding | EXP PMID:19781520 NMR structure of the transmembrane and cytoplasmic domains o... | MARK AS OVER ANNOTATED | Summary: EXP (DisProt) lipid binding, from NMR studies showing the amphipathic cytoplasmic helix of CD4 contacts micelle or microsomal membrane surfaces. Reason: Membrane-proximal association of an amphipathic helix in detergent micelles is a structural property of a transmembrane protein's tail, not a lipid-binding molecular function; the evidence does not identify a bound lipid ligand or a function that depends on it. Supporting Evidence: PMID:19781520 Experimental data suggest the amphipathic cytoplasmic helix to be in close contact with the micellar surface. |
| GO:0008289 lipid binding | EXP PMID:9622505 Solution structure of the cytoplasmic domain of the human CD... | MARK AS OVER ANNOTATED | Summary: EXP (DisProt) lipid binding, from NMR studies showing the amphipathic cytoplasmic helix of CD4 contacts micelle or microsomal membrane surfaces. Reason: Membrane-proximal association of an amphipathic helix in detergent micelles is a structural property of a transmembrane protein's tail, not a lipid-binding molecular function; the evidence does not identify a bound lipid ligand or a function that depends on it. Supporting Evidence: PMID:9622505 In keeping with this, CD4CYTO has the potential to associate with membranes as demonstrated by binding studies of in vitro phosphorylated CD4CYTO with microsomal membranes. |
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA is_active_in external side of plasma membrane, from the CD4 PAINT node with mouse, rat and human CD4 as sources. Reason: The ligand-binding D1-D4 ectodomain faces the extracellular space, which is precisely where the MHC class II interaction occurs, so is_active_in on the external side is apt. Supporting Evidence: PMID:11535811 The CD4 Phe-43 side chain extends into a hydrophobic concavity formed by MHC residues from both alpha 2 and beta 2 domains. PMID:2990730 The deduced protein sequence reveals that T4 is an integral membrane protein that shares significant amino acid and structural homologies with members of the immunoglobulin supergene family. |
| GO:0009897 external side of plasma membrane | IDA PMID:17213291 FcRL6, a new ITIM-bearing receptor on cytolytic cells, is br... | ACCEPT | Summary: IDA for external side of plasma membrane from flow-cytometric detection of surface CD4 on lymphocyte populations. Reason: Surface staining with ectodomain antibodies establishes the topology directly. Supporting Evidence: PMID:17213291 includes not only effector and effector-memory CD8(+) T cells but also populations of CD4(+) T cells PMID:2990730 The deduced protein sequence reveals that T4 is an integral membrane protein that shares significant amino acid and structural homologies with members of the immunoglobulin supergene family. |
| GO:0009897 external side of plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: IEA for external side of plasma membrane from combined automated methods. Reason: Consistent with the experimental rows and with the protein's type I membrane topology. Supporting Evidence: PMID:2990730 The deduced protein sequence reveals that T4 is an integral membrane protein that shares significant amino acid and structural homologies with members of the immunoglobulin supergene family. |
| GO:0009986 cell surface | IEA GO_REF:0000120 | ACCEPT | Summary: IEA for cell surface from combined automated methods. Reason: A correct, if less specific, statement of the same surface localization. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0010524 positive regulation of calcium ion transport into cytosol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA for positive regulation of calcium ion transport into cytosol, transferred from rat CD4. Reason: Calcium flux is a downstream output of the signaling CD4 helps initiate, through LCK, ZAP70 and PLCG1; CD4 does not itself act on a calcium channel or transporter, so this is a pathway consequence rather than a function CD4 performs. Supporting Evidence: file:human/CD4/CD4-uniprot.txt In turn, recruits the Src kinase LCK to the vicinity of the |
| GO:0015026 coreceptor activity | IDA PMID:2823150 Interaction between CD4 and class II MHC molecules mediates ... | ACCEPT | Summary: IDA for coreceptor activity, from the demonstration that CD4 binds class II MHC directly and increases the avidity of T cell-target cell interaction. Reason: Coreceptor activity is CD4's defining molecular function: it binds a non-polymorphic surface of peptide-MHC class II alongside the antigen-engaged TCR and, through its tail-bound LCK, raises the sensitivity of the receptor it serves. Supporting Evidence: PMID:2823150 Thus, the CD4 protein, even in the absence of T-cell receptor-antigen interactions, can interact directly with class II antigens to function as a cell surface adhesion molecule. file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. PMID:1901411 We demonstrate that, although CD4 and CD8 alpha can specifically enhance interleukin 2 secretion, maximal potentiation occurs with expression of CD4, which, unlike CD8, can bind to the same major histocompatibility complex protein as the T-cell receptor. file:human/CD4/CD4-deep-research-falcon.md CD4 is a **non-enzymatic receptor coreceptor**: its primary physiological role is to couple recognition of peptideβMHC class II by the T-cell receptor (TCR) to intracellular signaling. |
| GO:0015026 coreceptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA from the InterPro CD4 signature (IPR000973) for coreceptor activity. Reason: The family-level mapping matches the experimentally established function of the protein. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0015026 coreceptor activity | NAS PMID:8512039 Role of CD4 and CD8 in T cell activation and differentiation... | ACCEPT | Summary: NAS from a review of CD4 and CD8 in T cell activation, asserting coreceptor activity. Reason: The statement reflects the established consensus and is supported by primary experimental work on both the MHC class II interaction and the LCK coupling. Supporting Evidence: PMID:2823150 Thus, the CD4 protein, even in the absence of T-cell receptor-antigen interactions, can interact directly with class II antigens to function as a cell surface adhesion molecule. PMID:14500983 The T cell coreceptors CD4 and CD8 both associate via their cytoplasmic tails with the N-terminus of the Src-family tyrosine kinase Lck. |
| GO:0015026 coreceptor activity | TAS PMID:8674120 A dual-tropic primary HIV-1 isolate that uses fusin and the ... | ACCEPT | Summary: TAS for coreceptor activity cited to the identification of CKR-5/CCR5 as an HIV-1 entry cofactor. Reason: Coreceptor activity is correct for CD4 on independent grounds, and in the viral setting CD4 and the chemokine receptor act as the receptor-coreceptor pair for entry. Supporting Evidence: PMID:8674120 Expression of CKR-5 and CD4 enables entry of a M-tropic, but not a T-tropic, virus strain. PMID:9641677 The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: IEA from InterPro for the broad term membrane. Reason: Correct but unspecific; the plasma membrane and external-side rows carry the informative localization. Supporting Evidence: PMID:2990730 The deduced protein sequence reveals that T4 is an integral membrane protein that shares significant amino acid and structural homologies with members of the immunoglobulin supergene family. |
| GO:0019865 immunoglobulin binding | IEA GO_REF:0000107 | REMOVE | Summary: IEA transferred from rat CD4 by Ensembl Compara for immunoglobulin binding. Reason: There is no evidence that CD4 binds immunoglobulin. CD4 is itself built from immunoglobulin-like domains and binds the immunoglobulin-superfamily domains of MHC class II and of gp120, which is the likely origin of this transfer; the specific, supported terms are already present. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P05540 Β· Cd4 SOURCE BAD The rat donor annotation asserts immunoglobulin binding; CD4 contains Ig-like domains and binds Ig-superfamily ligands, which is not the same as binding an immunoglobulin. Supporting Evidence: PMID:2990730 The deduced protein sequence reveals that T4 is an integral membrane protein that shares significant amino acid and structural homologies with members of the immunoglobulin supergene family. file:human/CD4/CD4-uniprot.txt DOMAIN: The Ig-like V-type domain mediates the interaction with MHCII. |
| GO:0019899 enzyme binding | IPI PMID:19333378 The phospholipid scramblases 1 and 4 are cellular receptors ... | TOO GENERAL | Summary: Generic enzyme binding IPI for phospholipid scramblase 1 (PLSCR1). Reason: Enzyme binding is as uninformative as protein binding here: the cited work establishes PLSCR1 and PLSCR4 as SLPI receptors that also contact CD4, without defining a CD4 activity. TOO_GENERAL rather than REMOVE: protein tyrosine kinase binding, kept in this review, entails this term, so the claim is true but less informative. Supporting Evidence: PMID:19333378 At the molecular level, we show that SLPI is a ligand for both PLSCR1 and PLSCR4, and we reveal that PLSCR1 and PLSCR4 interact directly with the CD4 receptor at the cell surface of T lymphocytes. PMID:19333378 As expected, GFP-PLSCR1 and the endogenous CD4 antigen were both distributed at the plasma membrane in T cells |
| GO:0019901 protein kinase binding | IEA GO_REF:0000107 | MODIFY | Summary: IEA for protein kinase binding transferred from rat CD4. Reason: The conserved partner is the Src-family tyrosine kinase LCK, so the child term protein tyrosine kinase binding is both supported and more precise. Proposed replacements: protein tyrosine kinase binding Supporting Evidence: PMID:14500983 The T cell coreceptors CD4 and CD8 both associate via their cytoplasmic tails with the N-terminus of the Src-family tyrosine kinase Lck. PMID:3262426 Our data demonstrate that p56lck is specifically modulated with either CD4 or CD8 following antibody-mediated cross-linking of these molecules and that a large fraction of the total cellular lck protein can be coimmunoprecipitated with these surface glycoproteins. |
| GO:0019901 protein kinase binding | IPI PMID:7486703 Interaction of p56lck with CD4 in the yeast two-hybrid syste... | MODIFY | Summary: IPI for protein kinase binding from a yeast two-hybrid analysis of the p56lck-CD4 interaction. Reason: LCK is a protein tyrosine kinase; the specific child term states what is bound, and matches the reciprocal CD4 receptor binding annotation on LCK. Proposed replacements: protein tyrosine kinase binding Supporting Evidence: PMID:14500983 The T cell coreceptors CD4 and CD8 both associate via their cytoplasmic tails with the N-terminus of the Src-family tyrosine kinase Lck. PMID:9668045 These results are consistent with the proposal that Lck and CD4 associate by thiol-mediated co-coordination of zinc. |
| GO:0023026 MHC class II protein complex binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for MHC class II protein complex binding on the CD4 PAINT node, with human CD4 among the descendant evidences. Reason: MHC class II binding is the ancestral and defining ligand interaction of the CD4 family; the node placement is consistent with the experimental data in human, mouse and rat. Supporting Evidence: PMID:21900604 CD4 recognizes HLA-DR1 through its membrane-distal D1 domain, which contacts the membrane-proximal Ξ±2 and Ξ²2 domains of the MHC class II molecule PMID:2823150 Thus, the CD4 protein, even in the absence of T-cell receptor-antigen interactions, can interact directly with class II antigens to function as a cell surface adhesion molecule. |
| GO:0023026 MHC class II protein complex binding | IDA PMID:27114505 Remarkably low affinity of CD4/peptide-major histocompatibil... | ACCEPT | Summary: IDA from single-molecule and SPR measurement of the CD4/peptide-MHC class II interaction. Reason: Direct biophysical measurement of CD4 binding an intact class II complex; the remarkably low affinity is itself informative, since it implies CD4 works by being co-recruited with the TCR rather than by independent high-affinity ligation. Supporting Evidence: PMID:27114505 to measure the 2D K d for the CD4/pMHC II interaction, which proves to the best of our knowledge to be the weakest such interaction ever studied PMID:21900604 CD4 recognizes HLA-DR1 through its membrane-distal D1 domain, which contacts the membrane-proximal Ξ±2 and Ξ²2 domains of the MHC class II molecule |
| GO:0030217 T cell differentiation | IDA PMID:1533274 Signal for T-cell differentiation to a CD4 cell lineage is d... | KEEP AS NON CORE | Summary: IDA for T cell differentiation, from transgenic mice in which the CD4 transmembrane and cytoplasmic regions redirected class I-restricted thymocytes to the CD4 lineage. Reason: The experiment is strong, but it reports the developmental consequence of coreceptor signaling during thymic selection. Per the project rule that knockout and transgenic phenotypes record necessity rather than the step performed, this is kept as a non-core process. Supporting Evidence: PMID:1533274 Here we show that the CD4 transmembrane region and/or cytoplasmic tail mediates the delivery of a specific signal that directs differentiation of T cells to a CD4 lineage. PMID:9551897 These data also support the idea that a minimum avidity threshold for selection exists and that CD4 plays a crucial role in determining this avidity. |
| GO:0030225 macrophage differentiation | IMP PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage di... | KEEP AS NON CORE | Summary: IMP for macrophage differentiation, from CD4 ligation by MHC class II on human blood monocytes. Reason: Human monocytes, unlike mouse monocytes, express CD4, and its ligation by MHC-II on activated endothelium triggers MAPK- and Src-kinase-dependent differentiation into mature macrophages. This is a real TCR-independent role for CD4, kept as non-core relative to the helper T cell function. Supporting Evidence: PMID:24942581 We determined that the activation of CD4 via interaction with major histocompatibility complex class II (MHC-II) triggers cytokine expression and the differentiation of human monocytes into functional mature macrophages. PMID:24942581 Importantly, we determined that CD4 activation induces intracellular signaling in monocytes and that inhibition of the MAPK and Src family kinase pathways blocked the ability of CD4 ligation to trigger macrophage differentiation. file:human/CD4/CD4-uniprot.txt cells. In other cells such as macrophages or NK cells, plays a role in |
| GO:0030595 leukocyte chemotaxis | NAS PMID:27231345 Structure of a Potential Therapeutic Antibody Bound to Inter... | REMOVE | Summary: NAS for leukocyte chemotaxis, attached to a structural study of an anti-IL-16 therapeutic antibody. Reason: Chemotaxis is executed by the migrating cell's cytoskeletal and chemokine-receptor machinery, not by CD4, and the claim rests on the contested IL-16/CD4 ligand relationship -- the cited paper is in fact the one that failed to detect any IL-16-CD4 interaction by NMR or on CD4-expressing cells. Supporting Evidence: PMID:27231345 Surprisingly, in samples with a 5:1 molar excess of either CD4 D1βD4 or D3D4 we observed no shifts in the backbone amide signals of hIL-16, indicating no significant interaction between the two proteins under the experimental conditions used PMID:27231345 Attempts to directly or indirectly observe hIL-16 binding to cell lines expressing CD4 by flow cytometry also detected no interaction between CD4 and hIL-16 |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868658 | KEEP AS NON CORE | Summary: TAS from Reactome clathrin-mediated endocytosis reactions, placing CD4 in the clathrin-coated endocytic vesicle membrane as an AP-2 cargo. Reason: CD4 is a genuine clathrin/AP-2 cargo through the dileucine motif in its tail -- a route the virus exploits via Nef and that is masked when LCK is bound -- but this is receptor turnover rather than CD4's site of action. Supporting Evidence: PMID:8124721 Within this region, a dileucine motif, reminiscent of an endocytosis and lysosomal targeting signal found in the CD3 gamma and delta chains, is crucial for CD4 response to Nef. PMID:14500983 A dileucine motif required for clathrin-mediated endocytosis of CD4 is masked by Lck. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868659 | KEEP AS NON CORE | Summary: TAS from Reactome clathrin-mediated endocytosis reactions, placing CD4 in the clathrin-coated endocytic vesicle membrane as an AP-2 cargo. Reason: CD4 is a genuine clathrin/AP-2 cargo through the dileucine motif in its tail -- a route the virus exploits via Nef and that is masked when LCK is bound -- but this is receptor turnover rather than CD4's site of action. Supporting Evidence: PMID:8124721 Within this region, a dileucine motif, reminiscent of an endocytosis and lysosomal targeting signal found in the CD3 gamma and delta chains, is crucial for CD4 response to Nef. PMID:14500983 A dileucine motif required for clathrin-mediated endocytosis of CD4 is masked by Lck. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868660 | KEEP AS NON CORE | Summary: TAS from Reactome clathrin-mediated endocytosis reactions, placing CD4 in the clathrin-coated endocytic vesicle membrane as an AP-2 cargo. Reason: CD4 is a genuine clathrin/AP-2 cargo through the dileucine motif in its tail -- a route the virus exploits via Nef and that is masked when LCK is bound -- but this is receptor turnover rather than CD4's site of action. Supporting Evidence: PMID:8124721 Within this region, a dileucine motif, reminiscent of an endocytosis and lysosomal targeting signal found in the CD3 gamma and delta chains, is crucial for CD4 response to Nef. PMID:14500983 A dileucine motif required for clathrin-mediated endocytosis of CD4 is masked by Lck. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868661 | KEEP AS NON CORE | Summary: TAS from Reactome clathrin-mediated endocytosis reactions, placing CD4 in the clathrin-coated endocytic vesicle membrane as an AP-2 cargo. Reason: CD4 is a genuine clathrin/AP-2 cargo through the dileucine motif in its tail -- a route the virus exploits via Nef and that is masked when LCK is bound -- but this is receptor turnover rather than CD4's site of action. Supporting Evidence: PMID:8124721 Within this region, a dileucine motif, reminiscent of an endocytosis and lysosomal targeting signal found in the CD3 gamma and delta chains, is crucial for CD4 response to Nef. PMID:14500983 A dileucine motif required for clathrin-mediated endocytosis of CD4 is masked by Lck. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8869438 | KEEP AS NON CORE | Summary: TAS from Reactome clathrin-mediated endocytosis reactions, placing CD4 in the clathrin-coated endocytic vesicle membrane as an AP-2 cargo. Reason: CD4 is a genuine clathrin/AP-2 cargo through the dileucine motif in its tail -- a route the virus exploits via Nef and that is masked when LCK is bound -- but this is receptor turnover rather than CD4's site of action. Supporting Evidence: PMID:8124721 Within this region, a dileucine motif, reminiscent of an endocytosis and lysosomal targeting signal found in the CD3 gamma and delta chains, is crucial for CD4 response to Nef. PMID:14500983 A dileucine motif required for clathrin-mediated endocytosis of CD4 is masked by Lck. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871193 | KEEP AS NON CORE | Summary: TAS from Reactome clathrin-mediated endocytosis reactions, placing CD4 in the clathrin-coated endocytic vesicle membrane as an AP-2 cargo. Reason: CD4 is a genuine clathrin/AP-2 cargo through the dileucine motif in its tail -- a route the virus exploits via Nef and that is masked when LCK is bound -- but this is receptor turnover rather than CD4's site of action. Supporting Evidence: PMID:8124721 Within this region, a dileucine motif, reminiscent of an endocytosis and lysosomal targeting signal found in the CD3 gamma and delta chains, is crucial for CD4 response to Nef. PMID:14500983 A dileucine motif required for clathrin-mediated endocytosis of CD4 is masked by Lck. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871194 | KEEP AS NON CORE | Summary: TAS from Reactome clathrin-mediated endocytosis reactions, placing CD4 in the clathrin-coated endocytic vesicle membrane as an AP-2 cargo. Reason: CD4 is a genuine clathrin/AP-2 cargo through the dileucine motif in its tail -- a route the virus exploits via Nef and that is masked when LCK is bound -- but this is receptor turnover rather than CD4's site of action. Supporting Evidence: PMID:8124721 Within this region, a dileucine motif, reminiscent of an endocytosis and lysosomal targeting signal found in the CD3 gamma and delta chains, is crucial for CD4 response to Nef. PMID:14500983 A dileucine motif required for clathrin-mediated endocytosis of CD4 is masked by Lck. |
| GO:0032355 response to estradiol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA for response to estradiol, transferred from rat CD4 by Ensembl Compara. Reason: Orthology-transferred response-to-chemical annotations of this kind generally derive from rodent studies in which CD4 transcript or CD4+ cell numbers change after a treatment. A change in the abundance of CD4, or of the cells that bear it, is not CD4 performing a step of a response; nothing in the CD4 literature identifies a molecular role for the protein in handling these agents. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P05540 Β· Cd4 SOURCE WEAK OR INFERRED Rodent response-to-chemical annotations on CD4 track expression or cell-number changes rather than a function the protein performs. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0032507 maintenance of protein location in cell | IDA PMID:15128768 CD4 raft association and signaling regulate molecular cluste... | MODIFY | Summary: IDA acts_upstream_of_or_within maintenance of protein location in cell, from the finding that CD4 palmitoylation and signaling are required for TCR/PKC-theta raft association and clustering at the immunological synapse. Reason: The cited experiment is about organising receptors and PKC-theta at the synapse, not about holding a protein at a location against movement; immunological synapse formation is the process the evidence supports and CD4 contributes to it through its raft-targeted tail. Proposed replacements: immunological synapse formation Supporting Evidence: PMID:15128768 We show using transgenic mouse and retroviral reconstitution studies that CD4 is required for TCR/protein kinase C (PKC) theta clustering. PMID:15128768 Specifically, we demonstrate that CD4 palmitoylation sequences are required for TCR/PKCtheta raft association and subsequent clustering, indicating a particular role for raft-associated CD4 molecules in regulating immune synapse organization. |
| GO:0032743 positive regulation of interleukin-2 production | NAS PMID:1901411 Adhesion versus coreceptor function of CD4 and CD8: role of ... | KEEP AS NON CORE | Summary: NAS for positive regulation of interleukin-2 production, from the experiment comparing CD4, CD8 and tailless mutants in a class II-restricted T cell hybridoma. Reason: CD4 expression, and specifically its cytoplasmic tail, raises IL-2 secretion in response to antigen; this is a measured consequence of coreceptor function rather than a separate activity, so it is retained as non-core. Supporting Evidence: PMID:1901411 We demonstrate that, although CD4 and CD8 alpha can specifically enhance interleukin 2 secretion, maximal potentiation occurs with expression of CD4, which, unlike CD8, can bind to the same major histocompatibility complex protein as the T-cell receptor. |
| GO:0033280 response to vitamin D | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA for response to vitamin D, transferred from rat CD4 by Ensembl Compara. Reason: Orthology-transferred response-to-chemical annotations of this kind generally derive from rodent studies in which CD4 transcript or CD4+ cell numbers change after a treatment. A change in the abundance of CD4, or of the cells that bear it, is not CD4 performing a step of a response; nothing in the CD4 literature identifies a molecular role for the protein in handling these agents. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P05540 Β· Cd4 SOURCE WEAK OR INFERRED Rodent response-to-chemical annotations on CD4 track expression or cell-number changes rather than a function the protein performs. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0035397 helper T cell enhancement of adaptive immune response | IBA GO_REF:0000033 | ACCEPT | Summary: Helper T cell enhancement of adaptive immune response, by IBA on the CD4 node (with mouse Cd4) and by orthology-based IEA. Reason: This is the process CD4 exists for: by binding peptide-MHC class II alongside the TCR it sets the threshold for helper T cell activation and the cytokine output that follows, and loss of CD4 removes the conventional CD4+ helper compartment. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. PMID:1901411 We demonstrate that, although CD4 and CD8 alpha can specifically enhance interleukin 2 secretion, maximal potentiation occurs with expression of CD4, which, unlike CD8, can bind to the same major histocompatibility complex protein as the T-cell receptor. PMID:31781092 These findings support previous studies in CD4 KO mice suggesting that surrogate DN helper and regulatory T-cells capable of supporting antigen-specific immune responses are produced in the absence of CD4 signaling |
| GO:0035397 helper T cell enhancement of adaptive immune response | IEA GO_REF:0000107 | ACCEPT | Summary: Helper T cell enhancement of adaptive immune response, by IBA on the CD4 node (with mouse Cd4) and by orthology-based IEA. Reason: This is the process CD4 exists for: by binding peptide-MHC class II alongside the TCR it sets the threshold for helper T cell activation and the cytokine output that follows, and loss of CD4 removes the conventional CD4+ helper compartment. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. PMID:1901411 We demonstrate that, although CD4 and CD8 alpha can specifically enhance interleukin 2 secretion, maximal potentiation occurs with expression of CD4, which, unlike CD8, can bind to the same major histocompatibility complex protein as the T-cell receptor. PMID:31781092 These findings support previous studies in CD4 KO mice suggesting that surrogate DN helper and regulatory T-cells capable of supporting antigen-specific immune responses are produced in the absence of CD4 signaling |
| GO:0035723 interleukin-15-mediated signaling pathway | IBA GO_REF:0000033 | UNDECIDED | Summary: IBA for interleukin-15-mediated signaling pathway on the CD4 node, resting on the human IDA row. Reason: The CAFA-assigned IDA and the IBA that follows it place CD4 in interleukin-15-mediated signaling. The cached record for the cited paper is abstract-only and its abstract describes MHC class II ligation of CD4 on monocytes, cytokine expression and macrophage differentiation, with no mention of IL-15 either as a ligand of CD4 or as a pathway CD4 acts in. CD4 has no documented IL-15 binding activity and is not part of the IL-15 receptor, so the claim cannot be verified from what is available, and per policy it is left undecided rather than removed on the strength of an abstract. Since the IBA inherits from that unverifiable descendant evidence, it is left undecided on the same grounds. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN008967719 UNRESOLVED The node's assertion traces to the human CD4 IDA row, whose supporting publication is abstract-only here and does not mention IL-15. Supporting Evidence: PMID:24942581 We determined that the activation of CD4 via interaction with major histocompatibility complex class II (MHC-II) triggers cytokine expression and the differentiation of human monocytes into functional mature macrophages. |
| GO:0035723 interleukin-15-mediated signaling pathway | IDA PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage di... | UNDECIDED | Summary: IDA for interleukin-15-mediated signaling pathway from the CD4-ligation study on human monocytes. Reason: The CAFA-assigned IDA and the IBA that follows it place CD4 in interleukin-15-mediated signaling. The cached record for the cited paper is abstract-only and its abstract describes MHC class II ligation of CD4 on monocytes, cytokine expression and macrophage differentiation, with no mention of IL-15 either as a ligand of CD4 or as a pathway CD4 acts in. CD4 has no documented IL-15 binding activity and is not part of the IL-15 receptor, so the claim cannot be verified from what is available, and per policy it is left undecided rather than removed on the strength of an abstract. Supporting Evidence: PMID:24942581 We determined that the activation of CD4 via interaction with major histocompatibility complex class II (MHC-II) triggers cytokine expression and the differentiation of human monocytes into functional mature macrophages. PMID:24942581 Importantly, we determined that CD4 activation induces intracellular signaling in monocytes and that inhibition of the MAPK and Src family kinase pathways blocked the ability of CD4 ligation to trigger macrophage differentiation. |
| GO:0038023 signaling receptor activity | TAS PMID:10413516 Conformational changes of gp120 in epitopes near the CCR5 bi... | MODIFY | Summary: TAS for signaling receptor activity, cited to a biosensor study of CD4-induced conformational change in gp120. Reason: The cited work measures CD4 acting on the viral envelope, not CD4 transducing a signal as a primary receptor; virus receptor activity is what the reference supports. Proposed replacements: virus receptor activity Supporting Evidence: PMID:10413516 Adding soluble CD4 (sCD4) increased the association rate of full-length JR-FL gp120 by 25-fold. PMID:10922058 Accumulating biochemical and structural evidence indicates that, in addition to contributing to viral attachment, CD4 triggers conformational alterations in the HIV envelope that promote recognition of the chemokine receptors and ultimately lead to membrane fusion |
| GO:0042011 interleukin-16 binding | IPI PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage di... | UNDECIDED | Summary: Annotation of CD4 as the interleukin-16 receptor, derived from the classic report that CD4-affinity-purified lymphocyte chemoattractant factor triggers CD4-dependent calcium and IP3 signaling. Reason: The IL-16/CD4 relationship is genuinely contested. The original work shows CD4-dependent second-messenger generation and a reported sub-nanomolar affinity, but a later structural study failed to detect any interaction between mature IL-16 and the CD4 ectodomain by NMR or by competition with an anti-CD4 antibody on CD4-expressing cells. Neither result can be dismissed from the material available here -- monomeric versus multimeric IL-16 is the suggested reconciliation -- so the annotation is left undecided rather than accepted or removed. Supporting Evidence: PMID:1673145 These studies demonstrate direct interaction of a lymphokine with CD4 and generation of second messengers as a result of the interaction. PMID:27231345 Surprisingly, in samples with a 5:1 molar excess of either CD4 D1βD4 or D3D4 we observed no shifts in the backbone amide signals of hIL-16, indicating no significant interaction between the two proteins under the experimental conditions used PMID:27231345 Attempts to directly or indirectly observe hIL-16 binding to cell lines expressing CD4 by flow cytometry also detected no interaction between CD4 and hIL-16 |
| GO:0042012 interleukin-16 receptor activity | IDA PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage di... | UNDECIDED | Summary: Annotation of CD4 as the interleukin-16 receptor, derived from the classic report that CD4-affinity-purified lymphocyte chemoattractant factor triggers CD4-dependent calcium and IP3 signaling. Reason: The IL-16/CD4 relationship is genuinely contested. The original work shows CD4-dependent second-messenger generation and a reported sub-nanomolar affinity, but a later structural study failed to detect any interaction between mature IL-16 and the CD4 ectodomain by NMR or by competition with an anti-CD4 antibody on CD4-expressing cells. Neither result can be dismissed from the material available here -- monomeric versus multimeric IL-16 is the suggested reconciliation -- so the annotation is left undecided rather than accepted or removed. Supporting Evidence: PMID:1673145 These studies demonstrate direct interaction of a lymphokine with CD4 and generation of second messengers as a result of the interaction. PMID:27231345 Surprisingly, in samples with a 5:1 molar excess of either CD4 D1βD4 or D3D4 we observed no shifts in the backbone amide signals of hIL-16, indicating no significant interaction between the two proteins under the experimental conditions used PMID:27231345 Attempts to directly or indirectly observe hIL-16 binding to cell lines expressing CD4 by flow cytometry also detected no interaction between CD4 and hIL-16 |
| GO:0042101 T cell receptor complex | NAS PMID:8512039 Role of CD4 and CD8 in T cell activation and differentiation... | MARK AS OVER ANNOTATED | Summary: NAS part_of T cell receptor complex, from a review of CD4/CD8 function. Reason: CD4 is not a stoichiometric subunit of the TCR-CD3 complex: it is a separate single-chain coreceptor that is co-recruited to peptide-MHC class II, and the CD4-pMHCII-TCR geometry actually excludes a direct CD4-TCR contact. The functional association is better captured by the coreceptor activity, MHC class II binding and T cell receptor signaling pathway annotations. FRET between the cytosolic juxtamembrane regions of CD4 and CD3-delta does show that concurrent TCR and CD4 engagement of the same agonist pMHC brings them close together in a compact macrocomplex, but proximity on ligand engagement is not subunit membership. Supporting Evidence: PMID:11535811 This configuration excludes a direct TCR-CD4 interaction and suggests how TCR and CD4 signaling is coordinated around the antigenic pMHCII complex. PMID:27114505 to measure the 2D K d for the CD4/pMHC II interaction, which proves to the best of our knowledge to be the weakest such interaction ever studied PMID:27183595 indicating that concurrent TCR and CD4 engagement of agonist pMHC positions CD3Ξ΄ and CD4 in a cl PMID:27183595 Also of note, interactions between the SH2 domain of Lck and phosphorylated ITAMs would not contribute to the close association observed here since the clasp domain of CD4 that interacts with Lck was replaced by a FRET probe |
| GO:0042102 positive regulation of T cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA for positive regulation of T cell proliferation, transferred from rat CD4. Reason: Enhanced proliferation follows from CD4-assisted TCR signaling; keeping it non-core follows the project rule that lymphocyte-outcome terms record necessity rather than the step the protein performs. Supporting Evidence: PMID:1901411 We demonstrate that, although CD4 and CD8 alpha can specifically enhance interleukin 2 secretion, maximal potentiation occurs with expression of CD4, which, unlike CD8, can bind to the same major histocompatibility complex protein as the T-cell receptor. |
| GO:0042110 T cell activation | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for T cell activation on the CD4 node. Reason: CD4 participates directly in the activation step by stabilising the pMHCII-TCR engagement and supplying LCK; the node placement matches experimental data across mammals. Supporting Evidence: PMID:2823150 Thus, the CD4 protein, even in the absence of T-cell receptor-antigen interactions, can interact directly with class II antigens to function as a cell surface adhesion molecule. PMID:14500983 The T cell coreceptors CD4 and CD8 both associate via their cytoplasmic tails with the N-terminus of the Src-family tyrosine kinase Lck. |
| GO:0042289 MHC class II protein binding | IDA PMID:11535811 Crystal structure of the human CD4 N-terminal two-domain fra... | ACCEPT | Summary: IDA from the crystal structure of the CD4 D1D2 fragment bound to a class II MHC molecule. Reason: Atomic-resolution evidence that CD4 Phe43 inserts into a concavity formed by the MHC class II alpha-2 and beta-2 domains, defining the binding site precisely. Supporting Evidence: PMID:11535811 The CD4 Phe-43 side chain extends into a hydrophobic concavity formed by MHC residues from both alpha 2 and beta 2 domains. PMID:21900604 CD4 recognizes HLA-DR1 through its membrane-distal D1 domain, which contacts the membrane-proximal Ξ±2 and Ξ²2 domains of the MHC class II molecule file:human/CD4/CD4-uniprot.txt DOMAIN: The Ig-like V-type domain mediates the interaction with MHCII. |
| GO:0042289 MHC class II protein binding | IDA PMID:2823150 Interaction between CD4 and class II MHC molecules mediates ... | ACCEPT | Summary: IDA from the original cell-adhesion assay showing CD4-expressing cells bind class II-positive B cells. Reason: The founding direct evidence for the CD4-MHC class II interaction, with antibody-blocking and class II-negative mutant controls. Supporting Evidence: PMID:2823150 Thus, the CD4 protein, even in the absence of T-cell receptor-antigen interactions, can interact directly with class II antigens to function as a cell surface adhesion molecule. |
| GO:0042289 MHC class II protein binding | IPI PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage di... | ACCEPT | Summary: IPI for MHC class II protein binding with HLA-DRB1 and CD74 as partners, from the study of CD4 ligation on human monocytes. Reason: MHC class II engagement of CD4 is well established, and here it is shown to operate outside T cells, on monocytes, where MHC-II on activated endothelium ligates CD4. Supporting Evidence: PMID:24942581 We determined that the activation of CD4 via interaction with major histocompatibility complex class II (MHC-II) triggers cytokine expression and the differentiation of human monocytes into functional mature macrophages. PMID:2823150 Thus, the CD4 protein, even in the absence of T-cell receptor-antigen interactions, can interact directly with class II antigens to function as a cell surface adhesion molecule. |
| GO:0042289 MHC class II protein binding | NAS PMID:8512039 Role of CD4 and CD8 in T cell activation and differentiation... | ACCEPT | Summary: NAS for MHC class II protein binding from a review of CD4/CD8 function. Reason: The assertion matches the direct structural and biochemical evidence for the interaction. Supporting Evidence: PMID:11535811 The CD4 Phe-43 side chain extends into a hydrophobic concavity formed by MHC residues from both alpha 2 and beta 2 domains. |
| GO:0042802 identical protein binding | IPI PMID:9168119 Dimeric association and segmental variability in the structu... | MODIFY | Summary: IPI for identical protein binding, from the soluble CD4 crystal structures showing a dimeric association through the D4 domains. Reason: The specific child term protein homodimerization activity states what the evidence shows, a CD4-CD4 dimer, and is already annotated to the gene from the same and an independent study. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:9168119 These structures have a hinge-like variability at the D1D2 to D3D4 junction that might be important in immune recognition and HIV fusion, and a common dimeric association through D4 domains. PMID:9168119 Dynamic light scattering measurements and chemical crosslinking of sCD4 corroborate dimerization at high protein concentration. |
| GO:0042803 protein homodimerization activity | IDA PMID:12444132 CD4 dimers constitute the functional component required for ... | ACCEPT | Summary: IDA for protein homodimerization activity, with the dimer interface mapped to K318 and Q344 in the fourth extracellular domain and shown to be required for coreceptor function. Reason: Dimerization is a real, mapped property of CD4 and is functionally required: oligomerization is needed for stable class II binding, whereas monomeric CD4 suffices for gp120. Supporting Evidence: PMID:12444132 Using a series of point mutations, we have precisely mapped the dimerization site at residues K318 and Q344 within the fourth extracellular domain of CD4. PMID:12444132 More importantly, we demonstrate that dimer formation is essential for the coligand and coreceptor functions of CD4 in T cell activation. PMID:7604010 Expression of F43I results in a dominant negative effect: no class II MHC binding is observed even though wtCD4 expression is preserved. |
| GO:0042803 protein homodimerization activity | IDA PMID:9168119 Dimeric association and segmental variability in the structu... | ACCEPT | Summary: IDA for protein homodimerization activity from the soluble CD4 structures and solution measurements. Reason: Independent structural and biophysical support for the same D4-mediated homodimer. Supporting Evidence: PMID:9168119 These structures have a hinge-like variability at the D1D2 to D3D4 junction that might be important in immune recognition and HIV fusion, and a common dimeric association through D4 domains. PMID:9168119 Dynamic light scattering measurements and chemical crosslinking of sCD4 corroborate dimerization at high protein concentration. |
| GO:0045058 T cell selection | IDA PMID:9551897 The level of CD4 surface protein influences T cell selection... | KEEP AS NON CORE | Summary: IDA for T cell selection, from CD4-low mice in which reduced CD4 surface levels shift thymic selection of class II-restricted TCR transgenes. Reason: A genuine, dose-dependent contribution of CD4 to the avidity that drives positive and negative selection; retained as a developmental process downstream of the coreceptor function. Supporting Evidence: PMID:9551897 These data also support the idea that a minimum avidity threshold for selection exists and that CD4 plays a crucial role in determining this avidity. |
| GO:0045121 membrane raft | IBA GO_REF:0000033 | MODIFY | Summary: IBA is_active_in membrane raft on the CD4 node. Reason: Raft residence is functionally significant for CD4 -- palmitoylation of the two membrane-proximal cysteines plus LCK association concentrate it in rafts, and raft-localized CD4 is what enhances receptor tyrosine phosphorylation -- but the rafts concerned are plasma membrane rafts, so the more specific child term is used for all three rows on this term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN008967719 SUPPORTS TRANSFER Raft residence is correctly placed at the CD4 node; only the specificity of the compartment term is at issue. Proposed replacements: plasma membrane raft Supporting Evidence: PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. PMID:12517957 The localization of CD4 in lipid rafts also correlates to the ability of CD4 to enhance receptor tyrosine phosphorylation. file:human/CD4/CD4-uniprot.txt PTM: Palmitoylation and association with LCK contribute to the |
| GO:0045121 membrane raft | IDA PMID:9168119 Dimeric association and segmental variability in the structu... | MODIFY | Summary: IDA for membrane raft from detergent-resistant membrane fractionation of CD4 in T cells. Reason: The rafts in question are plasma membrane rafts, demonstrated at the T cell surface and dependent on palmitoylation of the membrane-proximal cysteines; the more specific term carries that information and matches the CD8A review. Proposed replacements: plasma membrane raft Supporting Evidence: PMID:12517957 By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. PMID:12517957 The localization of CD4 in lipid rafts also correlates to the ability of CD4 to enhance receptor tyrosine phosphorylation. |
| GO:0045121 membrane raft | IEA GO_REF:0000107 | MODIFY | Summary: IEA for membrane raft transferred from rat CD4. Reason: Raft localization is conserved and experimentally supported in human CD4; as for the other rows on this term, the specific child plasma membrane raft is used, matching the sibling CD8A review. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P05540 Β· Cd4 SUPPORTS TRANSFER Rat CD4 is a genuine ortholog and rafts are the right compartment; only the term's granularity changes. Proposed replacements: plasma membrane raft Supporting Evidence: file:human/CD4/CD4-uniprot.txt PTM: Palmitoylation and association with LCK contribute to the |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA for response to ethanol, transferred from rat CD4 by Ensembl Compara. Reason: Orthology-transferred response-to-chemical annotations of this kind generally derive from rodent studies in which CD4 transcript or CD4+ cell numbers change after a treatment. A change in the abundance of CD4, or of the cells that bear it, is not CD4 performing a step of a response; nothing in the CD4 literature identifies a molecular role for the protein in handling these agents. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P05540 Β· Cd4 SOURCE WEAK OR INFERRED Rodent response-to-chemical annotations on CD4 track expression or cell-number changes rather than a function the protein performs. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0045657 positive regulation of monocyte differentiation | IDA PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage di... | KEEP AS NON CORE | Summary: IDA for positive regulation of monocyte differentiation from the same CD4-ligation study. Reason: Same evidence as the macrophage differentiation row, stated as regulation of the monocyte side of the transition; retained as a non-core, cell-type-specific role. Supporting Evidence: PMID:24942581 We determined that the activation of CD4 via interaction with major histocompatibility complex class II (MHC-II) triggers cytokine expression and the differentiation of human monocytes into functional mature macrophages. PMID:24942581 Importantly, we determined that CD4 activation induces intracellular signaling in monocytes and that inhibition of the MAPK and Src family kinase pathways blocked the ability of CD4 ligation to trigger macrophage differentiation. |
| GO:0046718 symbiont entry into host cell | IDA PMID:9641677 Structure of an HIV gp120 envelope glycoprotein in complex w... | KEEP AS NON CORE | Summary: IDA for symbiont entry into host cell, from the gp120-CD4 structure defining the receptor-induced conformational change required for entry. Reason: CD4 performs the first step of HIV-1 entry: it binds gp120 and remodels the envelope to expose the chemokine-receptor site. The process is real and CD4 does the work, but it is a virus-exploited, non-physiological role and so is not part of the gene's core function. Supporting Evidence: PMID:9641677 The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. PMID:20080564 Binding of the initial receptor, CD4, induces changes in gp120 conformation that allow high-affinity interaction with the coreceptor, CCR5 or CXCR4, and the formation of a gp41 prehairpin intermediate. file:human/CD4/CD4-uniprot.txt Primary receptor for human file:human/CD4/CD4-deep-research-falcon.md CD4 is therefore the initial cellular HIV receptor, whereas **CCR5/CXCR4 are the HIV entry coreceptors**. |
| GO:0050729 positive regulation of inflammatory response | NAS PMID:9422780 Processing and activation of pro-interleukin-16 by caspase-3... | REMOVE | Summary: NAS for positive regulation of inflammatory response, cited to the demonstration that caspase-3 processes pro-IL-16 into the bioactive cytokine. Reason: The cited work concerns the maturation of IL-16 by caspase-3 and says nothing about a CD4 function; CD4 does not perform a step of inflammatory-response regulation. Supporting Evidence: PMID:9422780 Cleaved IL-16, but not pro-IL-16, exhibited lymphocyte chemoattractant activity. |
| GO:0050852 T cell receptor signaling pathway | IDA PMID:2823150 Interaction between CD4 and class II MHC molecules mediates ... | ACCEPT | Summary: IDA for T cell receptor signaling pathway, from the demonstration of direct CD4-class II interaction in the context of class II-restricted T cell recognition. Reason: CD4 performs a step of the pathway: it is co-recruited to the antigen-engaged receptor and delivers LCK, which phosphorylates the CD3 ITAMs. This is the core process annotation. Supporting Evidence: PMID:2823150 Thus, the CD4 protein, even in the absence of T-cell receptor-antigen interactions, can interact directly with class II antigens to function as a cell surface adhesion molecule. file:human/CD4/CD4-uniprot.txt In turn, recruits the Src kinase LCK to the vicinity of the PMID:14500983 The T cell coreceptors CD4 and CD8 both associate via their cytoplasmic tails with the N-terminus of the Src-family tyrosine kinase Lck. |
| GO:0050863 regulation of T cell activation | IDA PMID:1533274 Signal for T-cell differentiation to a CD4 cell lineage is d... | ACCEPT | Summary: IDA for regulation of T cell activation, from the CD8-CD4 hybrid transgenic experiment showing that the CD4 tail delivers a lineage-directing signal. Reason: CD4's contribution to the strength of antigen receptor signaling is well established and is mechanistically the same coreceptor function; the term is correct at an appropriate level. Supporting Evidence: PMID:1533274 Here we show that the CD4 transmembrane region and/or cytoplasmic tail mediates the delivery of a specific signal that directs differentiation of T cells to a CD4 lineage. PMID:1901411 We demonstrate that, although CD4 and CD8 alpha can specifically enhance interleukin 2 secretion, maximal potentiation occurs with expression of CD4, which, unlike CD8, can bind to the same major histocompatibility complex protein as the T-cell receptor. |
| GO:0050863 regulation of T cell activation | IEA GO_REF:0000117 | ACCEPT | Summary: IEA (ARBA) for regulation of T cell activation. Reason: Consistent with the experimental row and with the gene's established role. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0051240 positive regulation of multicellular organismal process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA (ARBA) for the very broad term positive regulation of multicellular organismal process. Reason: Not wrong, but so general that it conveys nothing specific about CD4. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:0097011 cellular response to granulocyte macrophage colony-stimulating factor stimulus | IDA PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage di... | UNDECIDED | Summary: IDA for cellular response to granulocyte macrophage colony-stimulating factor stimulus, from the CD4-ligation study on monocytes. Reason: GM-CSF is a standard component of monocyte-to-macrophage culture, and CD4 ligation was tested in that setting, but the cached abstract does not state what role CD4 plays in the response to GM-CSF and the full text is unavailable here. Left undecided rather than judged on the abstract. Supporting Evidence: PMID:24942581 We determined that the activation of CD4 via interaction with major histocompatibility complex class II (MHC-II) triggers cytokine expression and the differentiation of human monocytes into functional mature macrophages. |
| GO:1904313 response to methamphetamine hydrochloride | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA for response to methamphetamine hydrochloride, transferred from rat CD4 by Ensembl Compara. Reason: Orthology-transferred response-to-chemical annotations of this kind generally derive from rodent studies in which CD4 transcript or CD4+ cell numbers change after a treatment. A change in the abundance of CD4, or of the cells that bear it, is not CD4 performing a step of a response; nothing in the CD4 literature identifies a molecular role for the protein in handling these agents. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P05540 Β· Cd4 SOURCE WEAK OR INFERRED Rodent response-to-chemical annotations on CD4 track expression or cell-number changes rather than a function the protein performs. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:1904637 cellular response to ionomycin | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA for response to ionomycin, transferred from rat CD4 by Ensembl Compara. Reason: Orthology-transferred response-to-chemical annotations of this kind generally derive from rodent studies in which CD4 transcript or CD4+ cell numbers change after a treatment. A change in the abundance of CD4, or of the cells that bear it, is not CD4 performing a step of a response; nothing in the CD4 literature identifies a molecular role for the protein in handling these agents. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P05540 Β· Cd4 SOURCE WEAK OR INFERRED Rodent response-to-chemical annotations on CD4 track expression or cell-number changes rather than a function the protein performs. Supporting Evidence: file:human/CD4/CD4-uniprot.txt primarily as a coreceptor for MHC class II molecule:peptide complex. |
| GO:1990782 protein tyrosine kinase binding | IEA GO_REF:0000107 | ACCEPT | Summary: Protein tyrosine kinase binding: CD4's cytoplasmic tail binds the LCK unique region through a zinc clasp, and a large fraction of cellular LCK co-precipitates with CD4. Reason: This is one of CD4's two core molecular functions and the mechanistic basis of its coreceptor role: it delivers LCK to the peptide-MHC-engaged TCR. It is the mirror image of the GO:0042609 CD4 receptor binding annotation on LCK. Supporting Evidence: PMID:14500983 The T cell coreceptors CD4 and CD8 both associate via their cytoplasmic tails with the N-terminus of the Src-family tyrosine kinase Lck. PMID:14500983 The coreceptor tails and the Lck N-terminus are unstructured in isolation but assemble in the presence of zinc to form compactly folded heterodimeric domains. file:human/CD4/CD4-deep-research-falcon.md CD4 itself has **no catalytic activity**βLCK is the kinase. |
| GO:1990782 protein tyrosine kinase binding | IPI PMID:3262426 The CD4 and CD8 T cell surface antigens are associated with ... | ACCEPT | Summary: Protein tyrosine kinase binding: CD4's cytoplasmic tail binds the LCK unique region through a zinc clasp, and a large fraction of cellular LCK co-precipitates with CD4. Reason: This is one of CD4's two core molecular functions and the mechanistic basis of its coreceptor role: it delivers LCK to the peptide-MHC-engaged TCR. It is the mirror image of the GO:0042609 CD4 receptor binding annotation on LCK. Supporting Evidence: PMID:3262426 Our data demonstrate that p56lck is specifically modulated with either CD4 or CD8 following antibody-mediated cross-linking of these molecules and that a large fraction of the total cellular lck protein can be coimmunoprecipitated with these surface glycoproteins. PMID:9668045 These results are consistent with the proposal that Lck and CD4 associate by thiol-mediated co-coordination of zinc. file:human/CD4/CD4-deep-research-falcon.md CD4 itself has **no catalytic activity**βLCK is the kinase. |
| GO:0001772 immunological synapse | IDA PMID:15128768 CD4 raft association and signaling regulate molecular cluste... | NEW | Summary: Proposed new annotation placing CD4 at the immunological synapse, where raft-associated CD4 is required for TCR and PKC-theta clustering. Reason: CD4 is not merely required for synapse organisation; it is itself a constituent of the clustered structure, co-recruited with the TCR to peptide-MHC class II on the opposing cell and supplying LCK there. The cited work shows that CD4 palmitoylation sequences are needed for TCR/PKC-theta raft association and clustering at the synapse, and that raft targeting alone is insufficient without the signalling tail, which places CD4 in the structure rather than upstream of it. GOA currently records this only through a poorly fitting maintenance of protein location in cell row. Supporting Evidence: PMID:15128768 We show using transgenic mouse and retroviral reconstitution studies that CD4 is required for TCR/protein kinase C (PKC) theta clustering. PMID:15128768 Specifically, we demonstrate that CD4 palmitoylation sequences are required for TCR/PKCtheta raft association and subsequent clustering, indicating a particular role for raft-associated CD4 molecules in regulating immune synapse organization. PMID:12517957 The localization of CD4 in lipid rafts also correlates to the ability of CD4 to enhance receptor tyrosine phosphorylation. |
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Download this section (compressed HTML)Q: Is interleukin-16 a genuine ligand of CD4? The founding report shows CD4-dependent calcium and IP3 signaling by CD4-affinity-purified lymphocyte chemoattractant factor (PMID:1673145), but a later study detected no interaction between mature IL-16 and the CD4 ectodomain by NMR or on CD4-expressing cells (PMID:27231345), suggesting a requirement for multimeric IL-16. GO currently carries interleukin-16 binding and interleukin-16 receptor activity on CD4; should these be qualified or removed?
Q: What supports the interleukin-15-mediated signaling pathway annotations (GO:0035723, IDA and IBA) on CD4? The cited reference (PMID:24942581) is a study of MHC class II ligation of CD4 on human monocytes and its abstract does not mention IL-15, and CD4 is not a component of the IL-15 receptor.
Q: Should CD4 be part_of the T cell receptor complex (GO:0042101)? CD4 is a separate single-chain coreceptor rather than a stoichiometric subunit, and the CD4-pMHCII-TCR geometry excludes a direct CD4-TCR contact (PMID:11535811).
Q: Is there a GO term that captures CD4's role in organising the immunological synapse, where palmitoylation-dependent raft localization of CD4 is required for TCR and PKC-theta clustering (PMID:15128768)? The existing maintenance of protein location in cell annotation describes this poorly.
Q: How should GO treat CD4's non-T-cell role? MHC class II ligation of CD4 on human monocytes drives macrophage differentiation (PMID:24942581), a function that does not exist in mouse, where monocytes lack CD4 -- relevant when propagating annotations between the two species.
Q: Does the short CD4 isoform (isoform 2), which retains D4 and the LCK-binding tail but lacks the distal domains and so cannot bind HLA class II, have a function in vivo? It is expressed at the surface of patient T cells and enhances ZAP70 phosphorylation in vitro (PMID:38557723). If so, isoform-specific annotation would be needed, since the MHC class II binding and coreceptor terms apply only to the canonical isoform.
Q: Should GO distinguish CD4's microvillar-tip localization? CD4 accumulates at the tips of T cell microvilli in an LCK-dependent manner (PMID:31001252), which is proposed to be where first contact with MHC class II-bearing cells occurs; there is no obvious existing term for this sub-compartment of the plasma membrane.
Experiment: Resolve the IL-16/CD4 question directly: measure binding of monomeric versus defined oligomeric preparations of mature IL-16 to the CD4 ectodomain and to CD4 on intact cells by orthogonal methods (SPR, mass photometry, cell-surface binding), and test whether any binding requires the D1 or the D3/D4 domains.
Experiment: Separate coreceptor ligand binding from LCK delivery in a single system: reconstitute CD4-deficient primary human T cells with wild-type CD4, a Phe43 mutant that cannot bind class II, a tail-cysteine mutant that cannot form the zinc clasp, and a palmitoylation-site mutant, and quantify TCR sensitivity, ITAM phosphorylation kinetics and synapse clustering for each.
Experiment: Test whether CD4 dimerization is required in situ rather than only for soluble class II binding, by expressing the K318/Q344 dimerization-site mutants in primary T cells and measuring 2D affinity for peptide-MHC class II, LCK recruitment and antigen sensitivity.
Experiment: Define the monocyte pathway: in human monocytes, map which kinases are recruited to the CD4 tail after MHC class II ligation (LCK is low in monocytes), using proximity labelling plus tail-mutant rescue, and ask whether the zinc clasp is needed for macrophage differentiation.
Experiment: Characterise the immunological phenotype of human CD4 deficiency (immunodeficiency 79) in depth: compare antigen-specific responses, MHC class II restriction and TCR repertoire of the substituting double-negative T cells with conventional CD4+ T cells, to establish what CD4 contributes beyond lineage marking.
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