title: Increased Conformational Flexibility of HLA-B*27 Subtypes Associated With Ankylosing Spondylitis.
abstract: Dissimilarities in antigen processing and presentation are known to contribute to the differential association of HLA-B*27 subtypes with the inflammatory rheumatic disease ankylosing spondylitis (AS). In support of this notion, previous x-ray crystallographic data showed that peptides can be displayed by almost identical HLA-B*27 molecules in a subtype-dependent manner, allowing cytotoxic T lymphocytes to distinguish between these subtypes. For example, a human self-peptide derived from vasoactive intestinal peptide receptor type 1 (pVIPR; sequence RRKWRRWHL) is displayed in a single conformation by B*27:09 (which is not associated with AS), while B*27:05 (which is associated with AS) presents the peptide in a dual binding mode. In addition, differences in conformational flexibility between these subtypes might affect their stability or antigen presentation capability. This study was undertaken to investigate B*27:04 and B*27:06, another pair of minimally distinct HLA-B*27 subtypes, to assess whether dual peptide conformations or structural dynamics play a role in the initiation of AS.
  
  
  
  Using x-ray crystallography, we determined the structures of the pVIPR-B*27:04 and pVIPR-B*27:06 complexes and used isotope-edited infrared (IR) spectroscopy to probe the dynamics of these HLA-B*27 subtypes.
  
  
  
  As opposed to B*27:05 and B*27:09, B*27:04 (which is associated with AS) displays pVIPR conventionally and B*27:06 (which is not associated with AS) presents the peptide in a dual conformation. Comparison of the 4 HLA-B*27 subtypes using IR spectroscopy revealed that B*27:04 and B*27:05 possess elevated molecular dynamics compared to the nonassociated subtypes B*27:06 and B*27:09.
  
  
  
  Our results demonstrate that an increase in conformational flexibility characterizes the disease-associated subtypes B*27:04 and B*27:05.
authors.affiliation: Freie Universität Berlin, Berlin, Germany.
authors.forename: Bernhard
authors.identifier: 0000-0001-7928-4488
authors.initials: B
authors.lastname: Loll
authors.forename: Heinz
authors.initials: H
authors.lastname: Fabian
authors.affiliation: Charité-Universitätsmedizin Berlin and Freie Universität Berlin, Berlin, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Huser
authors.affiliation: Universität Basel, Basel, Switzerland.
authors.forename: Chee-Seng
authors.initials: CS
authors.lastname: Hee
authors.affiliation: Universität Bonn, Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ziegler
authors.affiliation: Charité-Universitätsmedizin Berlin and Freie Universität Berlin, Berlin, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Uchanska-Ziegler
authors.affiliation: Ziegler Biosolutions, Waldshut-Tiengen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
mesh_terms: D018360:Crystallography, X-Ray; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000737:chemistry / Q000378:metabolism*; D017550:Spectroscopy, Fourier Transform Infrared; D013167:Spondylitis, Ankylosing / Q000235:genetics* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: C510610:HLA-B*27:04 antigen; C510629:HLA-B*27:06 antigen; D015796:HLA-B27 Antigen; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C495506:VIPR1 protein, human