HLA-DR beta chain residue 86 controls DR alpha beta dimer stability

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Major histocompatibility complex (MHC) class II molecules present peptides to T cells.
• These molecules exist as SDS-stable and SDS-unstable alpha beta dimers, with varying ratios across different alleles.
• The molecular basis for these stability differences remained largely unknown.

Purpose of the Study:

• To investigate the molecular basis for the differential stability of MHC class II dimers.
• To determine the role of the valine/glycine dimorphism at position 86 in HLA-DR beta chains on dimer stability and peptide binding.

Main Methods:

• Analysis of SDS-stable and SDS-unstable alpha beta dimers from human HLA-DRB1 and HLA-DRB3 gene products.
• Reverse-phase high-performance liquid chromatography (RP-HPLC) to analyze peptides eluted from DR dimers.
• Comparison of DR dimers differing only at position 86 (Val86 vs. Gly86).

Main Results:

• The ratio of stable to unstable dimers is controlled by the valine/glycine dimorphism at position 86 of the DR beta chain.
• Haplotypes with Val86 express more stable dimers than those with Gly86.
• DR dimers with Val86 and Gly86 at position 86 bind distinct sets of peptides.
• The Val86 and Gly86 variants are not equally prevalent in the population, with preference depending on DR specificity.

Conclusions:

• The conserved dimorphism at HLA-DR beta chain position 86 significantly influences peptide selection and binding.
• This dimorphism provides the molecular basis for observed differences in SDS stability of DR dimers.
• The findings suggest a direct impact on antigen presentation by influencing peptide repertoire.