Beta 57-Asp plays an essential role in the unique SDS stability of HLA-DQA1*0102/DQB1*0602 alpha beta 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 alphabeta dimers and insulin-dependent diabetes mellitus (IDDM) susceptibility. The MHC class II alphabeta dimer encoded by HLA-DQA1*0102/DQB1*0602 (DQ0602), which is a dominant protective allele in IDDM, exhibits the greatest SDS 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-1. We addressed the molecular mechanism of the stability of DQ0602 in BLS-1. 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 beta57 was found to be critical for SDS stability, whereas Tyr at beta30, Gly at beta70, and Ala at beta86 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 SDS stability of DQ0602. These results support a role for DQB1 codon 57 in HLA-DQ alphabeta dimer stability and IDDM susceptibility.
Ettinger
R A
RA
Virginia Mason Research Center and Department of Immunology, University of Washington School of Medicine, Seattle, WA 98101, USA. ettinger@u.washington.edu
Liu
A W
AW
Nepom
G T
GT
Kwok
W W
WW
D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D001224:Aspartic Acid / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002461:Cell Line, Transformed; D002474:Cell-Free System / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D019281:Dimerization; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D012967:Sodium Dodecyl Sulfate
D000944:Antigens, Differentiation, B-Lymphocyte; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; C045084:invariant chain; D001224:Aspartic Acid; D012967:Sodium Dodecyl Sulfate