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Peptide exchange on MHC-I by TAPBPR is driven by a negative allostery release cycle.

  • Author(s): McShan, Andrew C
  • Natarajan, Kannan
  • Kumirov, Vlad K
  • Flores-Solis, David
  • Jiang, Jiansheng
  • Badstübner, Mareike
  • Toor, Jugmohit S
  • Bagshaw, Clive R
  • Kovrigin, Evgenii L
  • Margulies, David H
  • Sgourakis, Nikolaos G
  • et al.
Abstract

Chaperones TAPBPR and tapasin associate with class I major histocompatibility complexes (MHC-I) to promote optimization (editing) of peptide cargo. Here, we use solution NMR to investigate the mechanism of peptide exchange. We identify TAPBPR-induced conformational changes on conserved MHC-I molecular surfaces, consistent with our independently determined X-ray structure of the complex. Dynamics present in the empty MHC-I are stabilized by TAPBPR and become progressively dampened with increasing peptide occupancy. Incoming peptides are recognized according to the global stability of the final pMHC-I product and anneal in a native-like conformation to be edited by TAPBPR. Our results demonstrate an inverse relationship between MHC-I peptide occupancy and TAPBPR binding affinity, wherein the lifetime and structural features of transiently bound peptides control the regulation of a conformational switch located near the TAPBPR binding site, which triggers TAPBPR release. These results suggest a similar mechanism for the function of tapasin in the peptide-loading complex.

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