Molecular basis of MHC I quality control in the peptide loading complex

  • Nat Commun. 2022 Aug 10;13(1):4701. doi: 10.1038/s41467-022-32384-z.
Alexander Domnick  #  1 ,  Christian Winter  #  1 ,  Lukas Sušac  1 ,  Leon Hennecke  1 ,  Mario Hensen  2 ,  Nicole Zitzmann  2 ,  Simon Trowitzsch  1 ,  Christoph Thomas  1 ,  Robert Tampé  3
Affiliations
  • 1. Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt am Main, Germany.
  • 2. Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, OX1 3QU, Oxford, UK.
  • 3. Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt am Main, Germany. [email protected].
  • # Contributed equally.
PMID: 35948544 DOI: 10.1038/s41467-022-32384-z
Abstract

Major histocompatibility complex class I (MHC I) molecules are central to adaptive immunity. Their assembly, epitope selection, and antigen presentation are controlled by the MHC I glycan through a sophisticated network of chaperones and modifying Enzymes. However, the mechanistic integration of the corresponding processes remains poorly understood. Here, we determine the multi-chaperone-client interaction network of the peptide loading complex (PLC) and report the PLC editing module structure by cryogenic electron microscopy at 3.7 Å resolution. Combined with epitope-proofreading studies of the PLC in near-native lipid environment, these data show that peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan, which only becomes accessible for processing by α-glucosidase II upon loading of optimal epitopes. Our work reveals allosteric coupling between peptide-MHC I assembly and glycan processing. This inter-process communication defines the onset of an adaptive immune response and provides a prototypical example of the tightly coordinated events in endoplasmic reticulum quality control.