Erausquin, E.Serra, P.Parras, D.Santamaria, P.López Sagaseta, J.2024-01-302024-01-302022-07-281664-3224https://hdl.handle.net/2445/206648We recently provided evidence for promiscuous recognition of several different hybrid insulin peptides (HIPs) by the highly diabetogenic, I-Ag7-restricted 4.1-T cell receptor (TCR). To understand the structural determinants of this phenomenon, we solved the structure of an agonistic HIP/I-Ag7 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-Ag7 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-Ag7 structures reveals that 4.1-TCR binding triggers several novel and unique structural motions in both the I-Ag7 molecule and the peptide that are essential for docking. This observation indicates that the type 1 diabetes-associated I-Ag7 molecule is structurally malleable and that this plasticity allows the recognition of multiple peptides by individual TCRs that would otherwise be unable to do so.Copyright © 2022 Erausquin, Serra, Parras, Santamaria and López-Sagaseta.16 p.application/pdfengcc by (c) Erausquin, E. et al., 2022http://creativecommons.org/licenses/by/3.0/es/Seqüència d'aminoàcidsInsulinaAmino acid sequenceInsulininfo:eu-repo/semantics/article2023-06-28info:eu-repo/semantics/openAccess932892935967292