Location of CD4 dimerization site explains critical role of CDR3-like region in HIV-1 infection and T-cell activation and implies a model for complex of coreceptor-MHC.
CD4 cross-linking by antibodies or its natural ligands triggers a tyrosine kinase activity that is one of the necessary steps in the mechanism of human immunodeficiency virus type 1 (HIV-1)-induced syncytium formation and full Th-cell activation. In this study we mapped a part of the dimerization site of human CD4 to amino acids 87-98 using a bivalent CD4 immunoadhesin and a series of overlapping 12-mer peptides of the D1 domain. The dimerization site we found is part of the complementary determining region (CDR) 3-like region of CD4. Using the three-dimensional structure of other immunoglobulin dimers as a basis, a molecular modeling study was performed to dimerize the D1 domains of CD4. Both the peptide binding studies and molecular modeling studies independently led to the conclusion that the CDR3-like region is part of the CD4 dimerization site. The suggested dimerization of CD4 through its CDR3-like region explains the important role that has been ascribed to this region in Th-cell activation and HIV-1-mediated fusion. Based on this model of the CD4 dimer and published results of different mutational analysis studies, a model was proposed for the complex of the CD4 dimer with two MHC-II molecules. The CD4 dimer allows tight binding to a large surface of MHC-II and the complex of CD4 and MHC-II reconciles mutational analysis studies that were previously incompatible. Moreover, the complex suggests how CD4 can dimerize through ligand binding.
Langedijk
J P
JP
Central Veterinary Institute, Lelystad, The Netherlands.
Puijk
W C
WC
van Hoorn
W P
WP
Meloen
R H
RH
D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism*; D015726:Giant Cells / Q000382:microbiology; D015497:HIV-1 / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D014779:Virus Replication
D015704:CD4 Antigens; D000949:Histocompatibility Antigens Class II