Biochemistry & Molecular Pharmacology
Department of Biochemistry and Molecular Pharmacology; Department of Pathology
Medical Subject Headings
Protein Conformation; HLA-D Antigens; Histocompatibility Antigens; Genes, MHC Class II
Biochemistry, Biophysics, and Structural Biology | Chemistry | Life Sciences | Medicine and Health Sciences | Physical Sciences and Mathematics
HLA-DM is required for efficient peptide exchange on class II MHC molecules, but its mechanism of action is controversial. We trapped an intermediate state of class II MHC HLA-DR1 by substitution of αF54, resulting in a protein with increased HLA-DM binding affinity, weakened MHC-peptide hydrogen bonding as measured by hydrogen-deuterium exchange mass spectrometry, and increased susceptibility to DM-mediated peptide exchange. Structural analysis revealed a set of concerted conformational alterations at the N-terminal end of the peptide-binding site. These results suggest that interaction with HLA-DM is driven by a conformational change of the MHC II protein in the region of the α-subunit 3(10) helix and adjacent extended strand region, and provide a model for the mechanism of DM-mediated peptide exchange.
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Citation: Proc Natl Acad Sci U S A. 2011 Nov 29;108(48):19329-34. Link to article on publisher's website