The peptide-receptive transition state of MHC-1 molecules: Insight from structure and molecular dynamics
MHC class I (MHC-I) proteins of the adaptive immune system require antigenic peptides for maintenance of mature conformation and immune function via specific recognition by MHC-I-restricted CD8(+) T lymphocytes. New MHC-I molecules in the endoplasmic reticulum are held by chaperones in a peptide-receptive (PR) transition state pending release by tightly binding peptides. In this study, we show, by crystallographic, docking, and molecular dynamics methods, dramatic movement of a hinged unit containing a conserved 3(10) helix that flips from an exposed 'open' position in the PR transition state to a 'closed' position with buried hydrophobic side chains in the peptide-loaded mature molecule. Crystallography of hinged unit residues 46-53 of murine H-2L(d) MHC-I H chain, complexed with mAb 64-3-7, demonstrates solvent exposure of these residues in the PR conformation. Docking and molecular dynamics predict how this segment moves to help form the A and B pockets crucial for the tight peptide binding needed for stability of the mature peptide-loaded conformation, chaperone dissociation, and Ag presentation.
- Research Organization:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Organization:
- USDOE SC OFFICE OF BIOLOGICAL & ENVIRONMENTAL RESEARCH
- DOE Contract Number:
- DE-AC02-98CH10886
- OSTI ID:
- 1049231
- Report Number(s):
- BNL-98117-2012-JA; MOIMD5; R&D Project: BO-070; KP1605010; TRN: US201217%%566
- Journal Information:
- Molecular Immunology, Vol. 51, Issue 1; Conference: 7th International EMBO Workshop on Antigen Presentation and Processing; Amsterdam, The Netherlands; 20120424 through 20120427; ISSN 0161-5890
- Country of Publication:
- United States
- Language:
- English
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