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

HLA-B39:06, HLA-B39:01, and HLA-B38:01 are closely related HLA allotypes differentially associated with type 1 diabetes (T1D) risk and progression. B39:06 is highly predisposing, while B39:01 and B38:01 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 B39:06 and B39:01 allotypes had more rigid peptide-binding grooves and were more promiscuous in binding peptides than B38:01. Peptidomes of B39:06 and B39:01 contained fewer strong binders and were of lower affinity than that of B38:01. Experimentally, we demonstrated that B39:06 and B39:01 had a higher capacity to bind peptides and exit to the cell surface but lower surface levels and were degraded faster than B38:01. In summary, we propose that promiscuous B39:06 and B*39:01 may bind suboptimal peptides and transport them the cell surface, where such unstable complexes may contribute to the pathogenesis of T1D.