Differential association of HLA-B*2705 and B*2709 to ankylosing spondylitis correlates with limited peptide subsets but not with altered cell surface stability.
In contrast to HLA-B*2705, B*2709 is weakly or not associated to ankylosing spondylitis. Both allotypes differ by a single D116H change. We compared the B*2705- and B*2709-bound peptide repertoires by mass spectrometry to quantify the effect of B*2709 polymorphism on peptide specificity. In addition, shared and differentially bound ligands were sequenced to define the structural features of the various peptide subsets. B*2705 shared 79% of its peptide repertoire with B*2709. Shared ligands accounted for 88% of the B*2709-bound repertoire. All B*2705 ligands not bound to B*2709 had C-terminal basic or Tyr residues. Most B*2709-bound peptides had C-terminal aliphatic and Phe residues, but two showed C-terminal Arg or Tyr. The B*2709-bound repertoire included 12% of peptides not found in B*2705. These had aliphatic C-terminal residues, which are also favored in B*2705. However, these peptides bound weakly B*2705 in vitro, indicating distinct contribution of secondary anchor residues in both subtypes. Differences in peptide binding did not affect the ratio of native to beta2-microglobulin-free HLA-B27 heavy chain at the cell surface. Our results suggest that weaker association of B*2709 with ankylosing spondylitis is based on differential binding of a limited subset of natural ligands by this allotype.
Ramos
Manuel
M
Centro de Biologia Molecular Severo Ochoa, Universidad Autónoma de Madrid, Facultad de Ciencias, 28049 Madrid, Spain.
Paradela
Alberto
A
Vazquez
Miriam
M
Marina
Anabel
A
Vazquez
Jesus
J
Lopez de Castro
Jose A
JA
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001120:Arginine / Q000737:chemistry; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000939:Epitopes; D005434:Flow Cytometry; D015235:HLA-B Antigens / Q000737:chemistry*; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013167:Spondylitis, Ankylosing / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry
D000911:Antibodies, Monoclonal; D000939:Epitopes; D015235:HLA-B Antigens; C464936:HLA-B*27:05 antigen; C464937:HLA-B*27:09 antigen; D015796:HLA-B27 Antigen; D008024:Ligands; D010455:Peptides; D014443:Tyrosine; D004247:DNA; D001120:Arginine