In:
Arthritis & Rheumatology, Wiley, Vol. 68, No. 5 ( 2016-05), p. 1172-1182
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
2326-5191
,
2326-5205
Language:
English
Publisher:
Wiley
Publication Date:
2016
detail.hit.zdb_id:
2754614-7
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