Increased Conformational Flexibility of HLA-B*27 Subtypes Associated With Ankylosing Spondylitis.
- Loll B Freie Universität Berlin, Berlin, Germany.
- Fabian H Charité-Universitätsmedizin Berlin and Freie Universität Berlin, Berlin, Germany.
- Huser H Universität Basel, Basel, Switzerland.
- Hee CS Universität Bonn, Bonn, Germany.
- Ziegler A Charité-Universitätsmedizin Berlin and Freie Universität Berlin, Berlin, Germany.
- Uchanska-Ziegler B Ziegler Biosolutions, Waldshut-Tiengen, Germany.
- Ziegler A
- 2016-01-11
Published in:
- Arthritis & rheumatology (Hoboken, N.J.). - 2016
Crystallography, X-Ray
HLA-B27 Antigen
Humans
Molecular Conformation
Molecular Docking Simulation
Protein Binding
Protein Conformation
Receptors, Vasoactive Intestinal Polypeptide, Type I
Spectroscopy, Fourier Transform Infrared
Spondylitis, Ankylosing
T-Lymphocytes, Cytotoxic
English
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.
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1002/art.39567
- PMID 26748477
- Persistent URL
- https://sonar.ch/global/documents/174094
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