title: Loss of recognition by cross-reactive T cells and its relation to a C-terminus-induced conformational reorientation of an HLA-B*2705-bound peptide.
abstract: The human major histocompatibility complex class I antigen HLA-B*2705 binds several sequence-related peptides (pVIPR, RRKWRRWHL; pLPM2, RRRWRRLTV; pGR, RRRWHRWRL). Cross-reactivity of cytotoxic T cells (CTL) against these HLA-B*2705:peptide complexes seemed to depend on a particular peptide conformation that is facilitated by the engagement of a crucial residue within the binding groove (Asp116), associated with a noncanonical bulging-in of the middle portion of the bound peptide. We were interested whether a conformational reorientation of the ligand might contribute to the lack of cross-reactivity of these CTL with a peptide derived from voltage-dependent calcium channel α1 subunit (pCAC, SRRWRRWNR), in which the C-terminal peptide residue pArg9 could engage Asp116. Analyses of the HLA-B*2705:pCAC complex by X-ray crystallography at 1.94 Å resolution demonstrated that the peptide had indeed undergone a drastic reorientation, leading it to adopt a canonical binding mode accompanied by the loss of molecular mimicry between pCAC and sequence-related peptides such as pVIPR, pLMP2, and pGR. This was clearly a consequence of interactions of pArg9 with Asp116 and other F-pocket residues. Furthermore, we observed an unprecedented reorientation of several additional residues of the HLA-B*2705 heavy chain near the N-terminal region of the peptide, including also the presence of double conformations of two glutamate residues, Glu63 and Glu163, on opposing sides of the peptide binding groove. Together with the Arg-Ser exchange at peptide position 1, there are thus multiple structural reasons that may explain the observed failure of pVIPR-directed, HLA-B*2705-restricted CTL to cross-react with HLA-B*2705:pCAC complexes.
authors.affiliation: Institut für Chemie und Biochemie, Abteilung Strukturbiochemie, Freie Universität Berlin, Takustrasse 6, Berlin 14195, Germany. loll@chemie.fu-berlin.de
authors.forename: Bernhard
authors.initials: B
authors.lastname: Loll
authors.forename: Christine
authors.initials: C
authors.lastname: Rückert
authors.forename: Chee Seng
authors.initials: CS
authors.lastname: Hee
authors.forename: Wolfram
authors.initials: W
authors.lastname: Saenger
authors.forename: Barbara
authors.initials: B
authors.lastname: Uchanska-Ziegler
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
mesh_terms: D001665:Binding Sites; D015220:Calcium Channels / Q000737:chemistry; D003429:Cross Reactions; D018360:Crystallography, X-Ray; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry / Q000276:immunology*
chemical_list: D015220:Calcium Channels; D018984:Epitopes, T-Lymphocyte; C464936:HLA-B*27:05 antigen; D015796:HLA-B27 Antigen; D009842:Oligopeptides