CD4 OKTA4, T4, Leu 3a
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Lineage Restricted Molecule
Type 1 glycoprotein
T Cell
Neutrophil
Monocyte
Macrophage
T Lymphocyte
Granulocyte
Thymocyte
55 / 55

Expression
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.   

Structure
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.  

MOLECULAR MASS
Cell Type Unreduced Reduced
T lymphocytes 55 kDa 55 kDa

POST-TRANSCRIPTIONAL MODIFICATION

There is no alternate splicing.

POST-TRANSLATIONAL MODIFICATION

There are 2 N-linked glycosylation sites.

Ligands
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
Molecule Comment
MHC class II molecules Extracellular ligand for CD4
HIV envelope glycoprotein (gp120) Extracellular ligand for CD4
IL-16 Extracellular ligand for CD4
Human seminal plasma glycoprotein gp17/secretory actin-binding protein (SABP)/prolactin-inducible protein (PIP)/gross cystic disease fluid protein-15 (GCDFP-15)/extra-parotid glycoprotein (EP-GP) Extracellular ligand for CD4
p56lck Protein tyrosine kinase, intracellular ligand for CD4


 
 
 

Function
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.

Comments
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.

ADDITIONAL INSIGHTS

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
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 920P01730
MouseA02110P06332M13816
RatA27449P05540M15768
Antibodies
17D   View Reactivity
1F6   View Reactivity
2-35   View Reactivity
44.38   View Reactivity
74-12-4   View Reactivity
7E14   View Reactivity
BL4   View Reactivity
CA13.1E4   View Reactivity
CACT138A   View Reactivity
CACT83B   View Reactivity
CAT30A   View Reactivity
CC30   View Reactivity
CC8   View Reactivity
CT7   View Reactivity
CVS4   View Reactivity
DH29A   View Reactivity
GC17A   View Reactivity
GC1A   View Reactivity
GC50A1   View Reactivity
HB61A   View Reactivity
ILA11A   View Reactivity
KEN-4   View Reactivity
L200   View Reactivity
M-T477   View Reactivity
MT310   View Reactivity
PT90A   View Reactivity
RPA-T4   View Reactivity
RTH1A   View Reactivity
SFCI12T4D11   View Reactivity
SK3   View Reactivity
vpg34   View Reactivity
vpg38   View Reactivity
vpg39   View Reactivity
YKIX302.9   View Reactivity
YNB46.1.8   View Reactivity

Revised June 25, 2008


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