期刊
NATURE CHEMICAL BIOLOGY
卷 14, 期 8, 页码 811-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-018-0096-2
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资金
- Committee on Research (COR), Marquette University
- NIAID
- NIH
- K-22 Career Development
- R35 Outstanding Investigator Award through NIAID [AI2573-01]
- NIGMS [1R35GM125034-01]
- Office of the Director, NIH, under High End Instrumentation (HIE) Grant [S10OD018455]
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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