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

Area of Science:

• Immunogenetics
• Structural Biology
• Rheumatology

Background:

• Human Leukocyte Antigen (HLA) subtypes B*2705 and B*2709 differ by a single amino acid residue, yet show distinct associations with ankylosing spondylitis (AS).
• The molecular basis for this differential disease association remains unclear, potentially involving subtype-specific structural and dynamic properties.

Purpose of the Study:

• To investigate the structural and dynamic differences between HLA-B*2705 and HLA-B*2709.
• To explore the relationship between these molecular differences and the distinct disease associations of HLA-B27 subtypes.

Main Methods:

• In vitro expression and reconstitution of HLA-B27 heavy chains with beta(2)-microglobulin and peptides.
• Isotope-edited infrared spectroscopy was employed to analyze structure and flexibility at physiologic temperature.

Main Results:

• Subtype-specific conformational differences between HLA-B*2705 and HLA-B*2709 heavy chains were detected at physiologic temperature, not evident through X-ray crystallography.
• The HLA-B*2705 heavy chain demonstrated greater conformational flexibility compared to the B*2709 heavy chain, irrespective of the bound peptide.

Conclusions:

• Systematic conformational and dynamic differences exist between HLA-B27 subtypes B*2705 and B*2709.
• The differential flexibility of HLA-B27 heavy chains may play a role in the varying susceptibility to spondylarthritides observed among different HLA-B27 subtypes.