|CD4||OKTA4, T4, Leu 3a|
|Molecule Type||Antigen Expression||Molecular Weight|
Min / Max
|Lineage Restricted Molecule|
Type 1 glycoprotein
|55 / 55|
|CD4 is expressed on most thymocytes subsets and T lymphocyte subsets that recognize antigens associated with self-MHC class II molecules. It is expressed on peripheral blood monocytes, tissue macrophages and granulocytes in some species. It is also highly expressed on neutrophils in dogs. |
|MOLECULAR FAMILY NAME: Belongs to the immunoglobulin supergene family.|
CD4 is a single-pass type-1 glycoprotein. It contains a 370 aa extracellular domain which contains 3 Ig-like C2-type domains and 1 Ig-like V-type domain with domains 1, 2 and 4 being stabilized by disulphide bonds and domains 3 and 4 are N-linked glycosylation sites, a 25 aa transmembrane domain and a 38 aa cytoplasmic domain. The structures of the N-terminal 2 domains and separately, the membrane-proximal 2 domains, have been determined by X-ray crystallography, confirming that they are Ig-like. Domain 2 is characterized by an unusual disulfide within 1 b sheet and domain 3 lacks a disulfide in the position conserved in most IgSF domains. CD4 shows some unusual features with 17 residues inserted between domains 1 and 2. There is an additional Cys in domain 1 and the Cys in the unusual b strand C position in domain 2 is replaced with a Trp. There is an extra Cys in the b strand F. The position of the N-terminus has been established for the rat orthologue. CD4 shows particularly close similarities in overall structure to the LAG-3 protein. The cytoplasmic domain of CD4 is phosphorylated at Ser residues 408, 415, 431 when T cells are activated by antigen or phorbol esters.
There is no alternate splicing.
There are 2 N-linked glycosylation sites.
|CD4 domains 1 and 2 bind to MHC class II antigen. There is evidence that CD4 domains 3 and 4 are involved in cis interactions with the CD3/TCR complex. The cytoplasmic domain interacts with a lymphocyte-specific tyrosine kinase called Lck through a CXCP motif. CD4 is a receptor for HIV-1 and the binding of the viral gp120 protein is to a region of the N-terminal domain.|
LIGANDS AND MOLECULES ASSOCIATED WITH CD4
|CD4 has a role in cell-cell interactions and may act in signal transduction. CD4 is a co-receptor in MHC class II-restricted antigen-induced T cell activition. It regulates T and B lymphocyte adhesion in the absence of antigen recognition, in thymic differentiation and is the primary receptor for HIV retroviruses. Interactions with MHC class II and with Lck have shown to have a role in CD4 function. MAbs against CD4 inhibit T cell functions in vivo and in vitro. CD4 is a marker for regulating helper T cell recruitment to sites of inflammation as it is a receptor for pro-inflammatory cytokine IL-16. Binding seem to induce a migratory response in CD4+ cells particularly in the Th1 subset.|
BIOCHEMICAL ACTIVITY: No information.
DISEASE RELEVANCE AND FUNCTION OF CD4 IN INTACT ANIMAL
CD4 is used in monitoring progression of AIDS and serves as a receptor for HIV and may play a role in the accelerated level of T cell apoptosis during HIV infection as in vitro cross-linking of CD4 by HIV protein gp120 or anti-CD4 antibody leads to signaling via TCR-C3 and apoptosis of peripheral blood mononuclear cells from healthy individuals. A therapeutic antibody (Imuclone) is used for immunosuppression and treatment of psoriasis.
|MOLECULAR INTERACTIONS -|
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD4
CD4 contains transcriptional promoters and enhancers. The transcriptional cis-acting DNA elements have been identified by numerous authors. These sites have been defined by DH site analysis as well as extensive investigation into precise DNA sequence involved in the control of CD4. Some of the transcription factors that control CD4 have also been identified. These include the Ets and Myb proteins which act on the promoter, and HEB, TCF-1 a /LEF-1, and E12-related proteins which act on the 5' enhancer. An enhancer exists 13.5 kb 5' of the murine CD4 promoter and 6 kb 5' of the human CD4 promoter. Within the 1st intron 2 silencers exist. The region between the promoter and the 5' enhancer has a negative effect on transcription from the CD4 promoter. The transcriptional start sites have been defined and the human and murine promoters have been partially characterized.
SUBSTRATES: No information.
ENZYMES WHICH MODIFY CD4: No information.
CD4-mediated functions may require CD4 dimerization at CDR3 region 1 and at domain 4. Flexibility around the transmembrane-D4 linker region and the hinge region between D2 and D3 may be important for HIV infection and physiological function.
Database accession numbers
Revised June 25, 2008