title: HLA-B27 (B*2701) specificity for peptides lacking Arg2 is determined by polymorphism outside the B pocket.
abstract: B*2701 differs from B*2705-by three amino acid changes: D-->Y74, D-->N77, L-->A81, and from B*2702 only by two: D-->Y74 and T-->I80. Tyr74 is located in the C/F cavity of the peptide-binding site, and is unique to B*2701 among HLA-B27 subtypes. Binding of natural B*2705 and B*2702 ligands to B*2701, and to mutants mimicking subtype changes, was analyzed. In addition, sequencing of the peptides bound in vivo by B*2701 and the Y74 mutant was carried out. The main distinctive feature of B*2701 was its presentation of peptides with Gln2. Synthetic analogs bound in vitro similarly as the corresponding ligands with Arg2. Moreover, both Gln2 and Arg2 were dominant upon pool sequencing of B*2701-bound peptides, and 2 of 8 natural ligands contained Gln2. Suitability of Gln2 was largely determined by the Y74 change, as indicated by: 1) binding of Gln2 analogs to this mutant, and 2) detection of Gln2 by pool sequencing of Y74-bound peptides. B*2701 bound peptides with C-terminal aromatic or Leu residues, and interacted with these motifs more strongly than B*2702. The Y74 mutation alone was not responsible for poor binding of peptides with C-terminal basic residues to B*2701, since they bound efficiently and at least one was presented in vivo by this mutant. Most peptides bound to the A81 mutant worse than to B*2705, but frequently better than to B*2701 or B*2702, suggesting that other subtype changes were compensatory. The peptide specificity of B*2701 suggests that this subtype may determine susceptibility to spondyloarthropathy.
authors.affiliation: Centro de Biologia Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Facultad de Clencias, Spain.
authors.forename: F
authors.initials: F
authors.lastname: García
authors.forename: B
authors.initials: B
authors.lastname: Galocha
authors.forename: J A
authors.initials: JA
authors.lastname: Villadangos
authors.forename: J R
authors.initials: JR
authors.lastname: Lamas
authors.forename: J P
authors.initials: JP
authors.lastname: Albar
authors.forename: A
authors.initials: A
authors.lastname: Marina
authors.forename: J A
authors.initials: JA
authors.lastname: Lópaz de Castro
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D001120:Arginine / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology*; D011110:Polymorphism, Genetic
chemical_list: D015796:HLA-B27 Antigen; D010455:Peptides; D001120:Arginine