UniProt functional annotation for P01730



	UniProt functional annotation for P01730

UniProt code: P01730.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Integral membrane glycoprotein that plays an essential role in the immune response and serves multiple functions in responses against both external and internal offenses. In T-cells, functions primarily as a coreceptor for MHC class II molecule:peptide complex. The antigens presented by class II peptides are derived from extracellular proteins while class I peptides are derived from cytosolic proteins. Interacts simultaneously with the T-cell receptor (TCR) and the MHC class II presented by antigen presenting cells (APCs). In turn, recruits the Src kinase LCK to the vicinity of the TCR-CD3 complex. LCK then initiates different intracellular signaling pathways by phosphorylating various substrates ultimately leading to lymphokine production, motility, adhesion and activation of T-helper cells. In other cells such as macrophages or NK cells, plays a role in differentiation/activation, cytokine expression and cell migration in a TCR/LCK-independent pathway. Participates in the development of T- helper cells in the thymus and triggers the differentiation of monocytes into functional mature macrophages. {ECO:0000269|PubMed:16951326, ECO:0000269|PubMed:24942581, ECO:0000269|PubMed:2823150, ECO:0000269|PubMed:7604010}.

Function: (Microbial infection) Primary receptor for human immunodeficiency virus-1 (HIV-1) (PubMed:2214026, PubMed:16331979, PubMed:9641677, PubMed:12089508). Down-regulated by HIV-1 Vpu (PubMed:17346169). Acts as a receptor for Human Herpes virus 7/HHV-7 (PubMed:7909607). {ECO:0000269|PubMed:12089508, ECO:0000269|PubMed:16331979, ECO:0000269|PubMed:17346169, ECO:0000269|PubMed:2214026, ECO:0000269|PubMed:7909607, ECO:0000269|PubMed:9641677}.

Subunit: Forms disulfide-linked homodimers at the cell surface. Interacts with LCK (PubMed:16888650). Interacts with PTK2/FAK1 (PubMed:18078954). Binds to P4HB/PDI. Interacts with IL16; this interaction induces a CD4-dependent signaling in lymphocytes (PubMed:1673145). Interacts (via Ig-like V-type domain) with MHCII alpha chain (via alpha-2 domain) and beta chain (via beta-2 domain); this interaction increases the affinity of TCR for peptide-MHCII. CD4 oligomerization via Ig-like C2-type 2 and 3 domains appears to be required for stable binding to MHCII and adhesion between T cells and APCs (PubMed:27114505, PubMed:21900604, PubMed:7604010). {ECO:0000269|PubMed:11113139, ECO:0000269|PubMed:12089508, ECO:0000269|PubMed:1673145, ECO:0000269|PubMed:16888650, ECO:0000269|PubMed:18078954, ECO:0000269|PubMed:21900604, ECO:0000269|PubMed:27114505, ECO:0000269|PubMed:7604010}.

Subunit: (Microbial infection) Interacts with HIV-1 Envelope polyprotein gp160 and protein Vpu (PubMed:2214026, PubMed:16331979, PubMed:9641677, PubMed:7604010). {ECO:0000269|PubMed:16331979, ECO:0000269|PubMed:2214026, ECO:0000269|PubMed:7604010, ECO:0000269|PubMed:9641677}.

Subunit: (Microbial infection) Interacts with Human Herpes virus 7 surface proteins. {ECO:0000269|PubMed:7909607}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:12089508, ECO:0000269|PubMed:12517957, ECO:0000269|PubMed:2823150, ECO:0000269|PubMed:2990730}; Single-pass type I membrane protein {ECO:0000269|PubMed:12517957, ECO:0000269|PubMed:15340161, ECO:0000269|PubMed:1708753}. Note=Localizes to lipid rafts (PubMed:12517957, PubMed:9168119). Removed from plasma membrane by HIV- 1 Nef protein that increases clathrin-dependent endocytosis of this antigen to target it to lysosomal degradation. Cell surface expression is also down-modulated by HIV-1 Envelope polyprotein gp160 that interacts with, and sequesters CD4 in the endoplasmic reticulum.

Tissue specificity: Highly expressed in T-helper cells. The presence of CD4 is a hallmark of T-helper cells which are specialized in the activation and growth of cytotoxic T-cells, regulation of B cells, or activation of phagocytes. CD4 is also present in other immune cells such as macrophages, dendritic cells or NK cells. {ECO:0000269|PubMed:16951326, ECO:0000269|PubMed:24942581, ECO:0000269|PubMed:8088877}.

Domain: The Ig-like V-type domain mediates the interaction with MHCII. {ECO:0000269|PubMed:21900604, ECO:0000269|PubMed:7604010}.

Ptm: Palmitoylation and association with LCK contribute to the enrichment of CD4 in lipid rafts. {ECO:0000269|PubMed:1618861}.

Ptm: Phosphorylated by PKC; phosphorylation at Ser-433 plays an important role for CD4 internalization. {ECO:0000269|PubMed:2105883, ECO:0000269|PubMed:2512251}.

Polymorphism: The OKT monoclonal antibodies are widely used for the analysis of human peripheral blood T-lymphocytes. OKT4 reacts with T- helper/inducer lymphocytes. The OKT4 epitope of the CD4 cell-surface protein is polymorphic in white, black, and Japanese populations. The variable phenotypic expression is due a CD4 polymorphism. OKT4 positive individuals carry Arg-265 and OKT4 negative individuals carry Trp-265 [MIM:613949]. {ECO:0000269|PubMed:1708753, ECO:0000269|PubMed:1961196}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Integral membrane glycoprotein that plays an essential role in the immune response and serves multiple functions in responses against both external and internal offenses. In T-cells, functions primarily as a coreceptor for MHC class II molecule:peptide complex. The antigens presented by class II peptides are derived from extracellular proteins while class I peptides are derived from cytosolic proteins. Interacts simultaneously with the T-cell receptor (TCR) and the MHC class II presented by antigen presenting cells (APCs). In turn, recruits the Src kinase LCK to the vicinity of the TCR-CD3 complex. LCK then initiates different intracellular signaling pathways by phosphorylating various substrates ultimately leading to lymphokine production, motility, adhesion and activation of T-helper cells. In other cells such as macrophages or NK cells, plays a role in differentiation/activation, cytokine expression and cell migration in a TCR/LCK-independent pathway. Participates in the development of T- helper cells in the thymus and triggers the differentiation of monocytes into functional mature macrophages. {ECO:0000269\|PubMed:16951326, ECO:0000269\|PubMed:24942581, ECO:0000269\|PubMed:2823150, ECO:0000269\|PubMed:7604010}.



Function:		(Microbial infection) Primary receptor for human immunodeficiency virus-1 (HIV-1) (PubMed:2214026, PubMed:16331979, PubMed:9641677, PubMed:12089508). Down-regulated by HIV-1 Vpu (PubMed:17346169). Acts as a receptor for Human Herpes virus 7/HHV-7 (PubMed:7909607). {ECO:0000269\|PubMed:12089508, ECO:0000269\|PubMed:16331979, ECO:0000269\|PubMed:17346169, ECO:0000269\|PubMed:2214026, ECO:0000269\|PubMed:7909607, ECO:0000269\|PubMed:9641677}.


Subunit:		Forms disulfide-linked homodimers at the cell surface. Interacts with LCK (PubMed:16888650). Interacts with PTK2/FAK1 (PubMed:18078954). Binds to P4HB/PDI. Interacts with IL16; this interaction induces a CD4-dependent signaling in lymphocytes (PubMed:1673145). Interacts (via Ig-like V-type domain) with MHCII alpha chain (via alpha-2 domain) and beta chain (via beta-2 domain); this interaction increases the affinity of TCR for peptide-MHCII. CD4 oligomerization via Ig-like C2-type 2 and 3 domains appears to be required for stable binding to MHCII and adhesion between T cells and APCs (PubMed:27114505, PubMed:21900604, PubMed:7604010). {ECO:0000269\|PubMed:11113139, ECO:0000269\|PubMed:12089508, ECO:0000269\|PubMed:1673145, ECO:0000269\|PubMed:16888650, ECO:0000269\|PubMed:18078954, ECO:0000269\|PubMed:21900604, ECO:0000269\|PubMed:27114505, ECO:0000269\|PubMed:7604010}.
Subunit:		(Microbial infection) Interacts with HIV-1 Envelope polyprotein gp160 and protein Vpu (PubMed:2214026, PubMed:16331979, PubMed:9641677, PubMed:7604010). {ECO:0000269\|PubMed:16331979, ECO:0000269\|PubMed:2214026, ECO:0000269\|PubMed:7604010, ECO:0000269\|PubMed:9641677}.
Subunit:		(Microbial infection) Interacts with Human Herpes virus 7 surface proteins. {ECO:0000269\|PubMed:7909607}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:12089508, ECO:0000269\|PubMed:12517957, ECO:0000269\|PubMed:2823150, ECO:0000269\|PubMed:2990730}; Single-pass type I membrane protein {ECO:0000269\|PubMed:12517957, ECO:0000269\|PubMed:15340161, ECO:0000269\|PubMed:1708753}. Note=Localizes to lipid rafts (PubMed:12517957, PubMed:9168119). Removed from plasma membrane by HIV- 1 Nef protein that increases clathrin-dependent endocytosis of this antigen to target it to lysosomal degradation. Cell surface expression is also down-modulated by HIV-1 Envelope polyprotein gp160 that interacts with, and sequesters CD4 in the endoplasmic reticulum.
Tissue specificity:		Highly expressed in T-helper cells. The presence of CD4 is a hallmark of T-helper cells which are specialized in the activation and growth of cytotoxic T-cells, regulation of B cells, or activation of phagocytes. CD4 is also present in other immune cells such as macrophages, dendritic cells or NK cells. {ECO:0000269\|PubMed:16951326, ECO:0000269\|PubMed:24942581, ECO:0000269\|PubMed:8088877}.
Domain:		The Ig-like V-type domain mediates the interaction with MHCII. {ECO:0000269\|PubMed:21900604, ECO:0000269\|PubMed:7604010}.
Ptm:		Palmitoylation and association with LCK contribute to the enrichment of CD4 in lipid rafts. {ECO:0000269\|PubMed:1618861}.
Ptm:		Phosphorylated by PKC; phosphorylation at Ser-433 plays an important role for CD4 internalization. {ECO:0000269\|PubMed:2105883, ECO:0000269\|PubMed:2512251}.
Polymorphism:		The OKT monoclonal antibodies are widely used for the analysis of human peripheral blood T-lymphocytes. OKT4 reacts with T- helper/inducer lymphocytes. The OKT4 epitope of the CD4 cell-surface protein is polymorphic in white, black, and Japanese populations. The variable phenotypic expression is due a CD4 polymorphism. OKT4 positive individuals carry Arg-265 and OKT4 negative individuals carry Trp-265 [MIM:613949]. {ECO:0000269\|PubMed:1708753, ECO:0000269\|PubMed:1961196}.