Increased Conformational Flexibility of HLA–B*27 Subtypes Associated With Ankylosing Spondylitis. Issue 5 (May 2016)

• Record Type: Journal Article
• Authors: Loll, Bernhard; Fabian, Heinz; Huser, Hans; Hee, Chee‐Seng; Ziegler, Alexander; Uchanska‐Ziegler, Barbara; Ziegler, Andreas
• Is Part Of: Arthritis & rheumatology. Volume 68:Issue 5(2016)
• Page Start: 1172
• Page End: 1182
• Publication Date: 2016-05
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.39567
• Languages: English
• ISSNs: 2326-5191

Abstract

Abstract : 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.