Evidence for a domain-swapped CD4 dimer as the coreceptor for binding to class II MHC.
CD4 is a coreceptor for binding of T cells to APC and the primary receptor for HIV. The disulfide bond in the second extracellular domain (D2) of CD4 is reduced on the cell surface, which leads to formation of disulfide-linked homodimers. A large conformational change must take place in D2 to allow for formation of the disulfide-linked dimer. Domain swapping of D2 is the most likely candidate for the conformational change leading to formation of two disulfide-bonds between Cys130 in one monomer and Cys159 in the other one. Mild reduction of the extracellular part of CD4 resulted in formation of disulfide-linked dimers, which supports the domain-swapped model. The functional significance of dimer formation for coreceptor function was tested using cells expressing wild-type or disulfide-bond mutant CD4. Eliminating the D2 disulfide bond markedly impaired CD4's coreceptor function. Modeling of the complex of the TCR and domain-swapped CD4 dimer bound to class II MHC and Ag supports the domain-swapped dimer as the immune coreceptor. The known involvement of D4 residues Lys318 and Gln344 in dimer formation is also accommodated by this model. These findings imply that disulfide-linked dimeric CD4 is the preferred coreceptor for binding to APC.
Maekawa
Akiko
A
Centre for Vascular Research, University of New South Wales, Sydney, Australia.
Schmidt
Bryan
B
Fazekas de St Groth
Barbara
B
Sanejouand
Yves-Henri
YH
Hogg
Philip J
PJ
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D019281:Dimerization; D004220:Disulfides / Q000378:metabolism; D015804:HLA-DR4 Antigen / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010084:Oxidation-Reduction; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D012995:Solubility; D013879:Thioredoxins / Q000494:pharmacology
D015704:CD4 Antigens; D004220:Disulfides; D015804:HLA-DR4 Antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta; D013879:Thioredoxins