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Immunol."],"abstract":"<jats:p>We recently provided evidence for promiscuous recognition of several different hybrid insulin peptides (HIPs) by the highly diabetogenic, I-A<jats:sup>g7<\/jats:sup>-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<jats:sup>g7<\/jats:sup>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<jats:sup>g7<\/jats:sup>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\u2019s complementary determining regions. Surprisingly, comparison of the TCR-bound and unbound HIP\/I-A<jats:sup>g7<\/jats:sup>structures reveals that 4.1-TCR binding triggers several novel and unique structural motions in both the I-A<jats:sup>g7<\/jats:sup>molecule and the peptide that are essential for docking. This observation indicates that the type 1 diabetes-associated I-A<jats:sup>g7<\/jats:sup>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.<\/jats:p>","DOI":"10.3389\/fimmu.2022.924311","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T04:38:19Z","timestamp":1658983099000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Structural plasticity in I-Ag7 links autoreactivity to hybrid insulin peptides in type I 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