1. Peptide exchange on MHC-I by TAPBPR is driven by a negative allostery release cycle.
- Author
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McShan, Andrew C, 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, McShan, Andrew C, 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, and Sgourakis, Nikolaos G
- 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.
- Published
- 2018