7Z50

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

(2022) Front Immunol 13: 924311-924311

• PubMed: 35967292 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.3389/fimmu.2022.924311
• Primary Citation of Related Structures:  
  7QHP, 7Z50


• PubMed 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 4.1-TCR binding triggers several novel and unique structural motions in both the I-A ^g7 molecule and the peptide that are essential for docking. This observation indicates that the type 1 diabetes-associated I-A ^g7 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.

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Organizational Affiliation: 

Unit of Protein Crystallography and Structural Immunology, Navarrabiomed, Navarra, Spain.