title: Peptide handling by HLA-B27 subtypes influences their biological behavior, association with ankylosing spondylitis and susceptibility to endoplasmic reticulum aminopeptidase 1 (ERAP1).
abstract: HLA-B27 is strongly associated with ankylosing spondylitis (AS). We analyzed the relationship between structure, peptide specificity, folding, and stability of the seven major HLA-B27 subtypes to determine the role of their constitutive peptidomes in the pathogenicity of this molecule. Identification of large numbers of ligands allowed us to define the differences among subtype-bound peptidomes and to elucidate the peptide features associated with AS and molecular stability. The peptides identified only in AS-associated or high thermostability subtypes with identical A and B pockets were longer and had bulkier and more diverse C-terminal residues than those found only among non-AS-associated/lower-thermostability subtypes. Peptides sequenced from all AS-associated subtypes and not from non-AS-associated ones, thus strictly correlating with disease, were very rare. Residue 116 was critical in determining peptide binding, thermodynamic properties, and folding, thus emerging as a key feature that unified HLA-B27 biology. HLA-B27 ligands were better suited to TAP transport than their N-terminal precursors, and AS-associated subtype ligands were better than those from non-AS-associated subtypes, suggesting a particular capacity of AS-associated subtypes to bind epitopes directly produced in the cytosol. Peptides identified only from AS-associated/high-thermostability subtypes showed a higher frequency of ERAP1-resistant N-terminal residues than ligands found only in non-AS-associated/low-thermostability subtypes, reflecting a more pronounced effect of ERAP1 on the former group. Our results reveal the basis for the relationship between peptide specificity and other features of HLA-B27, provide a unified view of HLA-B27 biology and pathogenicity, and suggest a larger influence of ERAP1 polymorphism on AS-associated than non-AS-associated subtypes.
authors.affiliation: From the ‡Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid), Madrid, Spain;
authors.forename: Noel
authors.initials: N
authors.lastname: García-Medel
authors.affiliation: From the ‡Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid), Madrid, Spain;
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sanz-Bravo
authors.affiliation: From the ‡Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid), Madrid, Spain;
authors.forename: Carlos
authors.initials: C
authors.lastname: Alvarez-Navarro
authors.affiliation: From the ‡Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid), Madrid, Spain;
authors.forename: Patricia
authors.initials: P
authors.lastname: Gómez-Molina
authors.affiliation: §Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel;
authors.forename: Eilon
authors.initials: E
authors.lastname: Barnea
authors.affiliation: ¶Functional Proteomics Unit. Centro Nacional de Biotecnología (Consejo Superior de Investigaciones Científicas), Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Marcilla
authors.affiliation: §Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel;
authors.forename: Arie
authors.initials: A
authors.lastname: Admon
authors.affiliation: From the ‡Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid), Madrid, Spain; aldecastro@cbm.csic.es.
authors.forename: José A López
authors.initials: JA
authors.lastname: de Castro
mesh_terms: D000626:Aminopeptidases / Q000737:chemistry* / Q000378:metabolism; D002461:Cell Line, Transformed; D000939:Epitopes / Q000737:chemistry* / Q000378:metabolism; D015870:Gene Expression; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D008024:Ligands; D008214:Lymphocytes / Q000737:chemistry* / Q000166:cytology / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013167:Spondylitis, Ankylosing / Q000378:metabolism / Q000473:pathology; D013816:Thermodynamics
chemical_list: D000939:Epitopes; D015796:HLA-B27 Antigen; D008024:Ligands; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D020033:Protein Isoforms; D011994:Recombinant Proteins; D000626:Aminopeptidases; C464841:ERAP1 protein, human