Polymorphism in F pocket affects peptide selection and stability of type 1 diabetes-associated HLA-B39 allotypes.

ABSTRACT

HLA-B*3906, HLA-B*3901, and HLA-B*3801 are closely related HLA allotypes differentially associated with type 1 diabetes (T1D) risk and progression. B*3906 is highly predisposing, while B*3901 and B*3801 are weakly predisposing and protective allotypes, respectively. Here, we aimed to decipher molecular mechanisms underlying the differential association of these allotypes with T1D pathogenesis. We addressed peptide binding and conformational stability of HLA-B allotypes using computational and experimental approaches. Computationally, we found that B*3906 and B*3901 allotypes had more rigid peptide-binding grooves and were more promiscuous in binding peptides than B*3801. Peptidomes of B*3906 and B*3901 contained fewer strong binders and were of lower affinity than that of B*3801. Experimentally, we demonstrated that B*3906 and B*3901 had a higher capacity to bind peptides and exit to the cell surface but lower surface levels and were degraded faster than B*3801. In summary, we propose that promiscuous B*3906 and B*3901 may bind suboptimal peptides and transport them the cell surface, where such unstable complexes may contribute to the pathogenesis of T1D.