Conformation and solvent-accessibility of an MHC-I alpha-1 domain segment provide insight into the peptide receptive transition state (100.6)

Abstract MHC class I (MHC-I) molecules bound to antigenic peptides form the molecular structures recognized by MHC-I-restricted CD8+ T lymphocytes. On binding an antigenic peptide, the newly synthesized MHC-I sequesters a previously exposed region of the alpha-1 domain including residues 46-52, is released from tapasin, and proceeds to the cell surface. However, the changes in shape of MHC-I on peptide binding and release from tapasin remain unclear. We have determined four X-ray structures (from 1.64Å to 1.87 Å resolution) of an overlapping family of peptides from the H-2Ld alpha-1 domain (including residues 46-52) bound to the Fab fragment of 64-3-7, a mAb that reacts with peptide-receptive (PR) but not with peptide-loaded (PL) H-2Ld MHC-I. Positional differences of backbone and sidechain atoms of this alpha-1 domain segment, compared to the same segment in PL H-2Ld, indicate a significant conformational change on peptide loading. Among other changes, the side chain of the invariant Trp51 residue, and of Met52, although buried in PL MHCI, form extensive noncovalent bonds with mAb 64-3-7, indicating an external (solvent exposed) location in PR MHC-I. Furthermore, the 3(10) helix present in this segment of PL MHC-I is also present in the free peptide bound to MAb 64-3-7, and hence in the PR molecule. These findings help to delineate and provide insight into the conformational changes in MHC-I that accompany peptide loading. Supported by the intramural research program of the NIAID.