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

Hengameh Shams, Jill A Hollenbach, Atsuko Matsunaga, Mohammad R K Mofrad, Jorge R Oksenberg, Alessandro Didonna

Journal: Archives of biochemistry and biophysics 2022;719():109156

PMID: 35218721

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Abstract

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 α/β 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.

Address: Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, 94158, USA.; Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, 94158, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, 94158, USA.; Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, CA, 94720, USA.; Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, 94158, USA; Department of Anatomy and Cell Biology, East Carolina University, Greenville, NC, 27834, USA. Electronic address: [email protected].

DOI: 10.1016/j.abb.2022.109156