Molecular determinants of major histocompatibility complex class I complex stability: shaping antigenic features...

Area of Science:

• Immunology
• Structural Biology
• Computational Chemistry

Background:

• The human leukocyte antigen (HLA) B27 molecule is strongly associated with ankylosing spondylitis.
• Distinct HLA-B27 subtypes, such as HLA-B*2705 and HLA-B*2709, differ by a single amino acid (Asp-116/His) and may influence T cell repertoires and disease susceptibility.
• Understanding the molecular basis of these differences is crucial for elucidating disease pathogenesis.

Purpose of the Study:

• To investigate the role of electrostatic interactions in shaping antigenic differences between HLA-B*2705 and HLA-B*2709.
• To determine how these interactions affect peptide binding and complex stability with various peptide ligands.
• To correlate these molecular differences with the differential association of HLA-B27 subtypes with ankylosing spondylitis.

Main Methods:

• Fluorescence depolarization assays to measure peptide binding affinity and complex stability.
• pKa calculations to assess the protonation states of key residues within the HLA-B27 binding groove.
• Analysis of interactions between HLA-B27 subtypes and viral, self, and non-natural peptide ligands.

Main Results:

• A single amino acid substitution (Asp-116 in B*2705 vs. His-116 in B*2709) significantly impacts peptide binding.
• Specific interactions, such as Asp-116 with peptide residues at position 5, stabilize HLA-B*2705 complexes more than B*2709 complexes.
• Peptide- and subtype-dependent protonation of Glu-45 and Glu-63 in the B-pocket modulates the binding strength of the primary anchor residue (pArg-2).

Conclusions:

• Electrostatic interactions, including peptide- and subtype-dependent residue protonation, are critical determinants of HLA-B27 complex stability and antigenic presentation.
• These molecular variations contribute to distinct T cell recognition patterns associated with different HLA-B27 subtypes.
• The findings provide insights into the molecular mechanisms underlying the association of HLA-B27 subtypes with autoimmune diseases like ankylosing spondylitis.