Structural plasticity in I-A^g7 links autoreactivity to hybrid insulin peptides in type I diabetes.

ABSTRACT: We recently provided evidence for promiscuous recognition of several different hybrid insulin peptides (HIPs) by the highly diabetogenic, I-A^g7-restricted 4.1-T cell receptor (TCR). To understand the structural determinants of this phenomenon, we solved the structure of an agonistic HIP/I-A^g7 complex, both in isolation as well as bound to the 4.1-TCR. We find that HIP promiscuity of the 4.1-TCR is dictated, on the one hand, by an amino acid sequence pattern that ensures I-A^g7 binding and, on the other hand, by the presence of three acidic residues at positions P5, P7 and P8 that favor an optimal engagement by the 4.1-TCR's complementary determining regions. Surprisingly, comparison of the TCR-bound and unbound HIP/I-A^g7 structures reveals that 4.

SUBMITTER: Erausquin E 

PROVIDER: S-EPMC9365947 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature