Conformational lability in the class II MHC 310 helix and adjacent extended strand dictate HLA-DM susceptibility and peptide exchange.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 22084083.
- Also identified by DOI 10.1073/pnas.1108074108 and PMC identifier 3228433.
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Abstract
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.
Medical subject headings
- Antigen Presentation
- HLA-D Antigens
- HLA-DR1 Antigen
- Models, Molecular
- Peptides
- Protein Conformation