The peptide-receptive transition state of MHC-1 molecules: Insight from structure and molecular dynamics

• Published in: Molecular immunology Vol. 51; no. 1
• Main Authors: Robinson H., Mage, M., Dolan, M., Wang, R., Boyd, L., Revilleza, M., Natarajan, K., Myers, N., Hansen, T., Margulies, D.
• Format: Journal Article
• Language: English
• Published: United States 01.05.2012
• Subjects: 60 APPLIED LIFE SCIENCES; ANTIGENS; BASIC BIOLOGICAL SCIENCES; CHAINS; CRYSTALLOGRAPHY; DISSOCIATION; ENDOPLASMIC RETICULUM; LYMPHOCYTES; MAINTENANCE; MOLECULAR DYNAMICS METHOD; PEPTIDES; PROCESSING; PROTEINS; RESIDUES; SOLVENTS; STABILITY
• ISSN: 0161-5890; 1872-9142

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.