Dual, HLA-B27 Subtype-dependent Conformation of a Self-peptide

Author:

Hülsmeyer Martin1,Fiorillo Maria Teresa2,Bettosini Francesca2,Sorrentino Rosa2,Saenger Wolfram1,Ziegler Andreas3,Uchanska-Ziegler Barbara3

Affiliation:

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

Abstract

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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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