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

Raghavendra Anjanappa, Maria Garcia-Alai, Janine-Denise Kopicki, Julia Lockhauserbäumer, Mohamed Aboelmagd, Janina Hinrichs, Ioana Maria Nemtanu, Charlotte Uetrecht, Martin Zacharias, Sebastian Springer () and Rob Meijers ()
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Raghavendra Anjanappa: Jacobs University Bremen
Maria Garcia-Alai: European Molecular Biology Laboratory, Hamburg Outstation
Janine-Denise Kopicki: Heinrich Pette Institute, Leibniz Institute for Experimental Virology
Julia Lockhauserbäumer: Heinrich Pette Institute, Leibniz Institute for Experimental Virology
Mohamed Aboelmagd: Jacobs University Bremen
Janina Hinrichs: European Molecular Biology Laboratory, Hamburg Outstation
Ioana Maria Nemtanu: European Molecular Biology Laboratory, Hamburg Outstation
Charlotte Uetrecht: Heinrich Pette Institute, Leibniz Institute for Experimental Virology
Martin Zacharias: Technical University of Munich
Sebastian Springer: Jacobs University Bremen
Rob Meijers: European Molecular Biology Laboratory, Hamburg Outstation

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14862-4

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