Successive crystal structure snapshots suggest the basis for MHC class I peptide loading and editing by tapasin

Proceedings of the National Academy of Sciences of the United States of America
Ida HafstrandAdnane Achour

Abstract

MHC-I epitope presentation to CD8+ T cells is directly dependent on peptide loading and selection during antigen processing. However, the exact molecular bases underlying peptide selection and binding by MHC-I remain largely unknown. Within the peptide-loading complex, the peptide editor tapasin is key to the selection of MHC-I-bound peptides. Here, we have determined an ensemble of crystal structures of MHC-I in complex with the peptide exchange-associated dipeptide GL, as well as the tapasin-associated scoop loop, alone or in combination with candidate epitopes. These results combined with mutation analyses allow us to propose a molecular model underlying MHC-I peptide selection by tapasin. The N termini of bound peptides most probably bind first in the N-terminal and middle region of the MHC-I peptide binding cleft, upon which the peptide C termini are tested for their capacity to dislodge the tapasin scoop loop from the F pocket of the MHC-I cleft. Our results also indicate important differences in peptide selection between different MHC-I alleles.

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Citations

May 16, 2019·Critical Reviews in Biochemistry and Molecular Biology·Kannan NatarajanDavid H Margulies
Feb 1, 2020·Annual Review of Biophysics·Simon Trowitzsch, Robert Tampé
Aug 14, 2020·Proceedings of the National Academy of Sciences of the United States of America·Olivier FisetteLars V Schäfer
Jul 13, 2019·The Journal of Biological Chemistry·Ronja DrillerBernhard Loll
Oct 25, 2020·Proceedings of the National Academy of Sciences of the United States of America·Arman A BashirovaMary Carrington
Mar 11, 2021·Current Opinion in Immunology·Christoph Thomas, Robert Tampé
Mar 27, 2021·Frontiers in Immunology·Karthik DhatchinamoorthyKenneth L Rock
May 28, 2021·Nature Communications·Andrew C McShanNikolaos G Sgourakis
May 17, 2021·Current Opinion in Immunology·Nouria Jantz-Naeem, Sebastian Springer
May 31, 2021·Current Opinion in Immunology·Ida HafstrandLouise H Boyle
Jun 22, 2021·Current Opinion in Immunology·Hau V Truong, Nikolaos G Sgourakis
Sep 21, 2021·Molecular Immunology·F Tudor Ilca, Louise H Boyle

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