HLA-DR-BETA CHAIN RESIDUE 86 CONTROLS DR-ALPHA-BETA DIMER STABILITY

Major histocompatibility complex class II molecules exist in two forms ,which can be distinguished on the basis of their stability in sodium dodecyl sulfate (SDS) as SDS-stable and SDS-unstable alphabeta dimers. The ratio of stable vs. unstable alphabeta dimers varies between muri ne H-2 alleles and isotypes, but the molecular basis for this observat ion is unknown. Here we show that for the human HLA-DRB1 and HLA-DRB3 gene products this ratio is controlled by the valine/glycine dimorphis m at position 86. Haplotypes coding for DRbeta chains with a valine at position 86 express higher numbers of stable dimers compared to simil ar haplotypes expressing DRbeta chains with a glycine at that position . Reverse-phase high-performance liquid chromatography analysis of iod inated peptides, which were eluted from DR dimers with either a DRB11 101 or a DRB11104 beta chain which differ only at position 86, indic ated that these DR dimers contain (partially) distinct sets of peptide s. The valine/glycine dimorphism is highly conserved, present in most HLA-DR alleles and influences peptide-binding. Analysis of the occurre nce of the Val86 and the Gly86 gene products revealed that these are n ot equally present in the population. Depending on the DR specificity either the Val86 of Gly86 allelic variant is favored. Thus, the natura l, highly conserved dimorphism at HLA-DR beta chain position 86 influe nces peptide selection. The dimorphism is therefore likely to influenc e antigen presentation and forms the molecular basis for the observed differences in stability of Val86- and Gly86-containing DR dimers in t he presence of SDS.