β57-Asp plays an essential role in the unique SDS stability of HLA-DQA1*0102/DQB1*0602 αβ protein dimer, the class II MHC allele associated with protection from insulin-dependent diabetes mellitus

Studies of the stability of HLA-DQ have revealed a correlation between SDS stability of MHC class II alpha beta dimers and insulin-dependent diabetes mellitus (IDDM) susceptibility. The MHC class II alpha beta dinner encoded by HLA-DQA1*0102/DQB1*0602 (DQ0602), which is a dominant protective allele in IDDM, exhibits the greatest sos stability among HLA-DQ molecules in EBV-transformed B-lymphoblastoid cells and PBLs, DQ0602 is also uniquely SDS stable in the HLA-DM-deficient cell line, BLS-I, We addressed the molecular mechanism of the stability of DQ0602 in BLS-I, A panel of mutants based on the polymorphic differences between HLA-DQA1*0102/DQB1*0602 and HLA-DQA1*0102/DQB1*0604 were generated and expressed in BLS-1, An Asp at beta 57 was found to be critical for SDS stability, whereas Tyr at beta 30, Gly at beta 70, and Ala at beta 86 played secondary roles. Furthermore, the level of class II-associated invariant chain peptide bound to HLA-DQ did not correlate with SDS stability, suggesting that class II-associated invariant chain peptide does not play a direct role in the unique sos stability of DQ0602, These results support a role for DQB1 codon 57 in HLA-DQ alpha beta dimer stability and IDDM susceptibility.