title: Dual, HLA-B27 subtype-dependent conformation of a self-peptide.
abstract: The products of the human leukocyte antigen subtypes HLA-B*2705 and HLA-B*2709 differ only in residue 116 (Asp vs. His) within the peptide binding groove but are differentially associated with the autoimmune disease ankylosing spondylitis (AS); HLA-B*2705 occurs in AS-patients, whereas HLA-B*2709 does not. The subtypes also generate differential T cell repertoires as exemplified by distinct T cell responses against the self-peptide pVIPR (RRKWRRWHL). The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA-B*2705 molecules. In one binding mode, peptide pArg5 forms a salt bridge to Asp116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B*2709. These subtype-dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA-B*2705 or HLA-B*2709 to the buried Asp116/His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigens.
authors.affiliation: Institut für Kristallographie, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hülsmeyer
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Fiorillo
authors.forename: Francesca
authors.initials: F
authors.lastname: Bettosini
authors.forename: Rosa
authors.initials: R
authors.lastname: Sorrentino
authors.forename: Wolfram
authors.initials: W
authors.lastname: Saenger
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.forename: Barbara
authors.initials: B
authors.lastname: Uchanska-Ziegler
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013167:Spondylitis, Ankylosing / Q000235:genetics / Q000276:immunology; D055672:Static Electricity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D015235:HLA-B Antigens; C464936:HLA-B*27:05 antigen; C464937:HLA-B*27:09 antigen; D015796:HLA-B27 Antigen