The Journal of Experimental Medicine
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Published 20 January 2004. doi:10.1084/jem.20031690
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 2, 271-281
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Dual, HLA-B27 Subtype-dependent Conformation of a Self-peptide

Martin Hülsmeyer1, Maria Teresa Fiorillo2, Francesca Bettosini2, Rosa Sorrentino2, Wolfram Saenger1, Andreas Ziegler3, and Barbara Uchanska-Ziegler3

1 Institut für Kristallographie, Freie Universität Berlin,14195 Berlin, Germany
2 Dipartimento di Biologia Cellulare e dello Sviluppo, Università ‘La Sapienza,’ 00185 Roma, Italy
3 Institut für Immungenetik, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, 14050 Berlin, Germany

Address correspondence to Wolfram Saenger, Institut für Kristallographie, Freie Universität Berlin, 14195 Berlin, Germany. Phone: 49-30-8385-3412; Fax: 49-30-8385-6702; email: saenger{at}chemie.fu-berlin.de; or to Andreas Ziegler, Institut für Immungenetik, Charité, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, 14050 Berlin, Germany. Phone: 49-30-4505-53501; Fax: 49-30-4505-53953; email: andreas.ziegler{at}charite.de

The products of the human leukocyte antigen subtypes HLA-B*2705 and HLA-B*2709 differ only in residue 116 (Asp vs. His) within the peptide binding groove but are differentially associated with the autoimmune disease ankylosing spondylitis (AS); HLA-B*2705 occurs in AS-patients, whereas HLA-B*2709 does not. The subtypes also generate differential T cell repertoires as exemplified by distinct T cell responses against the self-peptide pVIPR (RRKWRRWHL). The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA-B*2705 molecules. In one binding mode, peptide pArg5 forms a salt bridge to Asp116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B*2709. These subtype-dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA-B*2705 or HLA-B*2709 to the buried Asp116/His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigens.

Key Words: X-ray structure • major histocompatibility antigen • peptide binding modes • ankylosing spondylitis • residue 116

Abbreviations used in this paper: AS, ankylosing spondylitis; ß2m, ß2-microglobulin; HC, heavy chain; rms, root mean square.


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