期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：5
页码：1505-1510
DOI：10.1073/pnas.1416543112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMHC class I molecules select and present a limited set of peptides from a broad repertoire provided by TAP. How MHC class I makes this selection is unclear. We show that MHC class I H-2Kb molecules initially bind many peptides because of highly flexible binding pockets. Peptide binding is followed by a selection step wherein a large fraction of these peptides is released, leaving the canonical peptides for presentation. The peptide presentation has a remarkable temperature dependency and explains the low-affinity peptides found associated to MHC class I molecules in cells cultured at low temperature. Our data suggest that MHC class I goes through rounds of considering and rejecting peptides until peptides with high affinity are acquired for presentation. MHC class I molecules present a variable but limited repertoire of antigenic peptides for T-cell recognition. Understanding how peptide selection is achieved requires mechanistic insights into the interactions between the MHC I and candidate peptides. We find that, at first encounter, MHC I H-2Kb considers a wide range of peptides, including those with expanded N termini and unfitting anchor residues. Discrimination occurs in the second step, when noncanonical peptides dissociate with faster exchange rates. This second step exhibits remarkable temperature sensitivity, as illustrated by numerous noncanonical peptides presented by H-2Kb in cells cultured at 26 {degrees}C relative to 37 {degrees}C. Crystallographic analyses of H-2Kb-peptide complexes suggest that a conformational adaptation of H-2Kb drives the decisive step in peptide selection. We propose that MHC class I molecules consider initially a large peptide pool, subsequently refined by a temperature-sensitive induced-fit mechanism to retain the canonical peptide repertoire.
