Definition of the α2 region of HLA-DR molecules involved in CD4 binding

• Published in: Human immunology 1999-04, Vol.60 (4), p.273-281
• Main Authors: Gaubin, Muriel, Houlgatte, Rémi, Dettin, Monica, Scarinci, Claudia, Martin, Michelle, Guardiola, John, Di Bello, Carlo, Piatier-Tonneau, Dominique
• Format: Article
• Language: English
• Subjects: affinity chromatography; circular dichroism; MHC class II-CD4 interaction; molecular modeling; peptide synthesis
• ISSN: 0198-8859; 1879-1166
• DOI: 10.1016/S0198-8859(98)00130-X

HLA class II molecules present antigenic peptides to the T cell receptor of CD4+ T lymphocytes and interact with CD4 during the antigen recognition process. A major CD4 binding site encompassing amino acids (aa) 134–148 in the β2 domain of HLA-DR has been previously identified and residues located within the α2 subunit of murine MHC class II I-A d molecules have been shown to contribute to CD4-class II interaction. To characterize the α2 region of HLA-DR molecules involved in the binding of CD4, we have synthesized overlapping linear and cyclic peptides derived from a region encompassing aa 121–143. We demonstrate that two linear peptides (aa 124–138 and 130–143) and a cyclic one (aa 121–138) specifically bind to CD4-sepharose affinity columns. Although cyclic analogues exhibit more ordered populations as detected by circular dichroism measurements, cyclization did not improve the activity of some peptides. Peptide sequence positioning in HLA-DR1 dimer model indicates that α2 residues 124 to 136 form a solvent-exposed loop which faces the β2 loop delimited by residues 134–148. These data suggest that one CD4 molecule contacts both α2 and β2 loops of the HLA-DR homodimer.