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

Alexander Domnick, Christian Winter, Lukas Sušac, Leon Hennecke, Mario Hensen, Nicole Zitzmann, Simon Trowitzsch, Christoph Thomas and Robert Tampé ()
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Alexander Domnick: Goethe University Frankfurt
Christian Winter: Goethe University Frankfurt
Lukas Sušac: Goethe University Frankfurt
Leon Hennecke: Goethe University Frankfurt
Mario Hensen: University of Oxford
Nicole Zitzmann: University of Oxford
Simon Trowitzsch: Goethe University Frankfurt
Christoph Thomas: Goethe University Frankfurt
Robert Tampé: Goethe University Frankfurt

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32384-z

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