HLA-B27 heavy chains distinguished by a micropolymorphism exhibit differential flexibility.

Abstract

OBJECTIVE:

Although the products of the HLA subtypes B*2705 and B*2709 differ only in residue 116 (Asp versus His) within their peptide-binding grooves, they are differentially associated with inflammatory rheumatic diseases such as ankylosing spondylitis (AS): B*2705 occurs in AS patients, whereas B*2709 is only rarely encountered. The reasons for this distinct association are still unclear but could include subtype-specific conformational and dynamic properties of these antigens. The present study was undertaken to investigate structural and dynamic differences between B*2705 and B*2709 and their possible relationship to subtype-specific disease association.

METHODS:

The membrane-distal segments of the B*2705 and B*2709 heavy chains were expressed in vitro and reconstituted together with beta(2)-microglobulin and a peptide. HLA-B27 complexes loaded with 2 self peptides (TIS [RRLPIFSRL] and pVIPR [RRKWRRWHL]) and a sequence-related viral peptide (pLMP2 [RRRWRRLTV]) were studied by isotope-edited infrared spectroscopy to detect differences in their structure and flexibility at physiologic temperature.

RESULTS:

Our analyses revealed the existence of subtype-specific conformational differences between the 2 HLA-B27 heavy chains at physiologic temperature, which are undetectable using x-ray crystallography. Irrespective of the bound peptide, the heavy chain of the B*2705 complex exhibited higher conformational flexibility than the B*2709 heavy chain.

CONCLUSION:

The present study demonstrates the existence of previously undetected systematic conformational and dynamic differences between the heavy chains of the 2 HLA-B27 subtypes. Since effector cell recognition of cells expressing HLA antigens is dependent on the dynamic properties of the interacting cell surface molecules, this HLA-B27 subtype-specific heavy chain flexibility could have a role in the distinct association of HLA-B27 subtypes with spondylarthritides.

• Authors: Heinz Fabian, Hans Huser, Bernhard Loll, Andreas Ziegler, Dieter Naumann, Barbara Uchanska-Ziegler
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 62 Issue 4 Pg. 978-87 (Apr 2010) ISSN: 1529-0131 [Electronic] United States
• PMID: 20131248 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-B27 Antigen
• Peptide Fragments

Topics

• Amino Acid Sequence
• Amino Acid Substitution
• Escherichia coli (immunology)
• HLA-B27 Antigen (chemistry, genetics)
• Humans
• Inclusion Bodies (genetics, immunology)
• Models, Molecular
• Peptide Fragments (chemistry)
• Polymorphism, Genetic
• Protein Conformation
• Spectrophotometry, Infrared
• Spondylarthritis (genetics, immunology)