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Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/206648
Structural plasticity in I-Ag7 links autoreactivity to hybrid insulin peptides in type I diabetes
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We 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.
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ERAUSQUIN, E., et al. Structural plasticity in I-Ag7 links autoreactivity to hybrid insulin peptides in type I diabetes. Frontiers In Immunology. 2022. Vol. 13, num. 924311. ISSN 1664-3224. [consulted: 12 of August of 2026]. Available at: https://hdl.handle.net/2445/206648