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Increased Conformational Flexibility of HLA–B*27 Subtypes Associated With Ankylosing Spondylitis
Author(s) -
Loll Bernhard,
Fabian Heinz,
Huser Hans,
Hee CheeSeng,
Ziegler Alexander,
UchanskaZiegler Barbara,
Ziegler Andreas
Publication year - 2016
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39567
Subject(s) - hla b , peptide , ankylosing spondylitis , human leukocyte antigen , peptide conformation , hla b27 , chemistry , hla b antigens , crystallography , biology , antigen , immunology , biochemistry
Objective Dissimilarities in antigen processing and presentation are known to contribute to the differential association of HLA–B*27 subtypes with the inflammatory rheumatic disease ankylosing spondylitis (AS). In support of this notion, previous x‐ray crystallographic data showed that peptides can be displayed by almost identical HLA–B*27 molecules in a subtype‐dependent manner, allowing cytotoxic T lymphocytes to distinguish between these subtypes. For example, a human self‐peptide derived from vasoactive intestinal peptide receptor type 1 (pVIPR; sequence RRKWRRWHL) is displayed in a single conformation by B*27:09 (which is not associated with AS), while B*27:05 (which is associated with AS) presents the peptide in a dual binding mode. In addition, differences in conformational flexibility between these subtypes might affect their stability or antigen presentation capability. This study was undertaken to investigate B*27:04 and B*27:06, another pair of minimally distinct HLA–B*27 subtypes, to assess whether dual peptide conformations or structural dynamics play a role in the initiation of AS. Methods Using x‐ray crystallography, we determined the structures of the pVIPR–B*27:04 and pVIPR–B*27:06 complexes and used isotope‐edited infrared (IR) spectroscopy to probe the dynamics of these HLA–B*27 subtypes. Results As opposed to B*27:05 and B*27:09, B*27:04 (which is associated with AS) displays pVIPR conventionally and B*27:06 (which is not associated with AS) presents the peptide in a dual conformation. Comparison of the 4 HLA–B*27 subtypes using IR spectroscopy revealed that B*27:04 and B*27:05 possess elevated molecular dynamics compared to the nonassociated subtypes B*27:06 and B*27:09. Conclusion Our results demonstrate that an increase in conformational flexibility characterizes the disease‐associated subtypes B*27:04 and B*27:05.