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Structures of peptide-free and partially loaded MHC class I molecules reveal mechanisms of peptide selection.

ABSTRACT: Major Histocompatibility Complex (MHC) class I molecules selectively bind peptides for presentation to cytotoxic T cells. The peptide-free state of these molecules is not well understood. Here, we characterize a disulfide-stabilized version of the human class I molecule HLA-A*02:01 that is stable in the absence of peptide and can readily exchange cognate peptides. We present X-ray crystal structures of the peptide-free state of HLA-A*02:01, together with structures that have dipeptides bound in the A and F pockets. These structural snapshots reveal that the amino acid side chains lining the binding pockets switch in a coordinated fashion between a peptide-free unlocked state and a peptide-bound locked state. Molecular dynamics simulations suggest that the opening and closing of the F pocket affects peptide ligand conformations in adjacent binding pockets. We propose that peptide binding is co-determined by synergy between the binding pockets of the MHC molecule.

SUBMITTER: Anjanappa R

PROVIDER: S-EPMC7066147 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Native mass spectrometry of peptide-free and partially loaded MHC class I molecules

Project description:A disulfide-stabilized MHC class I molecule (HLA-A*02:01(Y84C/A139C), short dsA2) was characterized by native mass spectrometry. dsA2 was shown to be structurally intact in absence of any peptide whereas its wild type form was not. Furthermore, it was observed that the mutation did not disrupt the binding of cognate peptides.

2022-05-11 | PXD016708 | Pride

Whole genome duplications have provided teleosts with many roads to peptide loaded MHC class I molecules.

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