Dual, HLA-B27 subtype-dependent conformation of a self-peptide.
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.
Hülsmeyer
Martin
M
Institut für Kristallographie, Freie Universität Berlin, 14195 Berlin, Germany.
Fiorillo
Maria Teresa
MT
Bettosini
Francesca
F
Sorrentino
Rosa
R
Saenger
Wolfram
W
Ziegler
Andreas
A
Uchanska-Ziegler
Barbara
B
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013167:Spondylitis, Ankylosing / Q000235:genetics / Q000276:immunology; D055672:Static Electricity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D015235:HLA-B Antigens; C464936:HLA-B*27:05 antigen; C464937:HLA-B*27:09 antigen; D015796:HLA-B27 Antigen