A short HLA-DRA isoform binds the HLA-DR2 heterodimer on the outer domain of the peptide-binding site

The human leukocyte antigen (HLA) locus encodes a large group of proteins governing adaptive and innate immune responses. Among them, HLA class II proteins form alpha/beta heterodimers on the membrane of professional antigen-presenting cells (APCs), where they display both, self and pathogen-derived exogenous antigens to CD4(+) T lymphocytes. We have previously shown that a shorter HLA-DRA isoform (sHLA-DRA) lacking 25 amino acids can be presented onto the cell membrane via binding to canonical HLA-DR2 heterodimers. Here, we employed atomistic molecular dynamics simulations to decipher the binding position of sHLA-DRA and its structural impact on functional regions of the HLA-DR2 molecule. We show that a loop region exposed only in the short isoform (residues R69 to G83) is responsible for binding to the outer domain of the HLA-DR2 peptide-binding site, and experimentally validated the critical role of F76 in mediating such interaction. Additionally, sHLA-DRA allosterically modifies the peptide-binding pocket conformation. In summary, this study unravels key molecular mechanisms underlying sHLA-DRA function, providing important insights into the role of full-length proteins in structural modulation of HLA class II receptors.

Automated summary

This study used atomistic molecular dynamics simulations to unravel the binding position of sHLA-DRA and its impact on the structure of HLA-DR2. It was found that a loop region in the short isoform is responsible for binding to the peptide-binding site of HLA-DR2, and F76 plays a critical role in mediating this interaction. Additionally, sHLA-DRA modifies the conformation of the peptide-binding pocket.