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Originally published In Press as doi:10.1074/jbc.M104663200 on July 2, 2001
J. Biol. Chem., Vol. 276, Issue 35, 32729-32737, August 31, 2001
Identification of Novel HLA-B27 Ligands Derived from Polymorphic
Regions of Its Own or Other Class I Molecules Based on Direct
Generation by 20 S Proteasome*
Iñaki
Alvarez ,
Laura
Sesma ,
Miguel
Marcilla ,
Manuel
Ramos ,
Mercè
Martí ,
Emilio
Camafeita§, and
José A. López
de Castro ¶
From the Centro de Biología Molecular Severo
Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Facultad
de Ciencias, and the § Centro Nacional de
Biotecnología, 28049 Madrid, Spain
HLA-B27 is strongly associated with ankylosing
spondylitis. Natural HLA-B27 ligands derived from polymorphic regions
of its own or other class I HLA molecules might be involved in
autoimmunity or provide diversity among HLA-B27-bound peptide
repertoires from individuals. In particular, an 11-mer spanning
HLA-B27 residues 169-179 is a natural HLA-B27 ligand with
homology to proteins from Gram-negative bacteria. Proteasomal digestion
of synthetic substrates demonstrated direct generation of the
B27-(169-179) ligand. Cleavage after residue 181 generated a
B27-(169-181) 13-mer that was subsequently found as a natural ligand
of B*2705 and B*2704. Its binding to HLA-B27 subtypes in
vivo correlated better than B27-(169-179) with association to
spondyloarthropathy. Proteasomal cleavage generated also a peptide
spanning B*2705 residues 150-158. This region is polymorphic among
HLA-B27 subtypes and class I HLA antigens. The peptide was a natural
B*2704 ligand. Since this subtype differs from B*2705 at residue 152, it was concluded that the ligand arose from HLA-B*3503, synthesized in
the cells used as a source for B*2704-bound peptides. Thus, polymorphic
HLA-B27 ligands derived from HLA-B27 or other class I molecules are
directly produced by the 20 S proteasome in vitro, and this
can be used for identification of such ligands in the constitutive
HLA-B27-bound peptide pool.
*
This work was supported by Grants SAF99/0055 from the Plan
Nacional de I+D, PM99-0098 from the Ministry of Science and Technology, and 08.3/0022/1998 from the Comunidad Autónoma de Madrid and an
institutional grant to the Centro de Biología Molecular
Severo Ochoa from the Fundación Ramón Areces.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
¶
To whom correspondence should be addressed: Centro de
Biología Molecular Severo Ochoa, Universidad
Autónoma de Madrid, Facultad de Ciencias, Cantoblanco, 28049 Madrid, Spain. Tel.: 34-91-397-80-50; Fax: 34-91-397-80-87; E-Mail:
aldecastro@cbm.uam.es.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.
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