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Originally published In Press as doi:10.1074/jbc.M108882200 on October 22, 2001

J. Biol. Chem., Vol. 276, Issue 52, 48740-48747, December 28, 2001
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The Cys-67 Residue of HLA-B27 Influences Cell Surface Stability, Peptide Specificity, and T-cell Antigen Presentation*

Iñaki AlvarezDagger , Mercè MartíDagger , Jesús VázquezDagger , Emilio Camafeita§, Samuel OguetaDagger , and José A. López de CastroDagger

From the Dagger  Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas), Universidad Autónoma de Madrid, Facultad de Ciencias and § Centro Nacional de Biotecnología, 28049 Madrid, Spain

Cys-67 of HLA-B27 is located in the B pocket, which determines peptide-binding specificity. We analyzed effects of the Cys-67 right-arrow Ser mutation on cell surface expression, peptide specificity, and T-cell recognition of HLA-B*2705. Surface expression was assessed with antibodies recognizing either native or unfolded HLA proteins. Whereas native B*2705 molecules predominated over unfolded ones, this ratio was reversed in the mutant, suggesting lower stability. Comparison of B*2705- and Cys-67 right-arrow Ser-bound peptides revealed that the mutant failed to bind ~15% of the B*2705 ligands, while binding as many novel ones. Two peptides with Gln-2 found in both B*2705 and Cys-67 right-arrow Ser are the first demonstration of natural B*2705 ligands lacking Arg-2. Other effects of the mutation on peptide specificity were: 1) average molecular mass of natural ligands higher than for B*2705, 2) bias against small residues at peptide position (P) 1, and 3) increased P2 permissiveness. The results suggest that the Cys-67 right-arrow Ser mutation weakens B pocket interactions, leading to decreased stability of the mutant-peptide complexes. This may be partially compensated by interactions involving bulky P1 residues. The effect of the mutation on allorecognition was consistent with that on peptide specificity. Our results may aid understanding of the pathogenetic role of HLA-B27 in spondyloarthropathy.

* This work was supported by Grant SAF99/0055 from the Plan Nacional de Investigacion y Desarrollo, Grant PM99-0098 from the Ministry of Science and Technology, and an institutional grant from the Fundación Ramón Areces (to the Centro de Biología Molecular Severo Ochoa).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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