Title
Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors
Author
Charles L. Dulberger, Curtis P. McMurtrey, Angelique Hölzemer, Karlynn E. Neu, Victor Liu, Adriana M. Steinbach, Wilfredo F. Garcia-Beltran, Michael Sulak, Bana Jabri, Vincent J. Lynch, Marcus Altfeld, William H. Hildebrand, Erin J. Adams
Year
2017
Journal
Immunity
Abstract
Evidence is mounting that the major histocompatibility complex (MHC) molecule HLA-F (human leukocyte antigen F) regulates the immune system in pregnancy, infection, and autoimmunity by signaling through NK cell receptors (NKRs). We present structural, biochemical, and evolutionary analyses demonstrating that HLA-F presents peptides of unconventional length dictated by a newly arisen mutation (R62W) that has produced an open-ended groove accommodating particularly long peptides. Compared to empty HLA-F open conformers (OCs), HLA-F tetramers bound with human-derived peptides differentially stained leukocytes, suggesting peptide-dependent engagement. Our in vitro studies confirm that NKRs differentiate between peptide-bound and peptide-free HLA-F. The complex structure of peptide-loaded β2m-HLA-F bound to the inhibitory LIR1 revealed similarities to high-affinity recognition of the viral MHC-I mimic UL18 and a docking strategy that relies on contacts with HLA-F as well as β2m, thus precluding binding to HLA-F OCs. These findings provide a biochemical framework to understand how HLA-F could regulate immunity via interactions with NKRs.
Instrument
J-1500
Keywords
Circular dichroism, Secondary structure, Thermal stability, Protein denaturation, Thermodynamics, Biochemistry