Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding

DOI: 10.1038/s41467-018-05459-z

Authors: Lucy C. Walters (University of Oxford) , Karl Harlos (Wellcome Trust Centre for Human Genetics, University of Oxford) , Simon Brackenridge (Wellcome Trust Centre for Human Genetics, University of Oxford) , Daniel Rozbesky (Wellcome Centre for Human Genetics, University of Oxford) , Jordan R. Barrett (University of Oxford) , Vitul Jain (Wellcome Centre for Human Genetics, University of Oxford) , Thomas S. Walter (Wellcome Centre for Human Genetics, University of Oxford) , Chris A. O’callaghan (University of Oxford) , Persephone Borrow (University of Oxford) , Mireille Toebes (Netherlands Cancer Institute) , Scott G. Hansen (Oregon Health & Science University) , Jonah Sacha (Oregon Health & Science University) , Shaheed Abdulhaqq (Oregon Health & Science University) , Justin M. Greene (Oregon Health & Science University) , Klaus Früh (Oregon Health & Science University) , Emily Marshall (Oregon Health & Science University) , Louis J. Picker (Oregon Health & Science University) , E. Yvonne Jones (Wellcome Centre for Human Genetics, University of Oxford) , Andrew J. Mcmichael (University of Oxford) , Geraldine M. Gillespie (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 9

State: Published (Approved)
Published: August 2018
Diamond Proposal Number(s): 14744

Abstract: Through major histocompatibility complex class Ia leader sequence-derived (VL9) peptide binding and CD94/NKG2 receptor engagement, human leucocyte antigen E (HLA-E) reports cellular health to NK cells. Previous studies demonstrated a strong bias for VL9 binding by HLA-E, a preference subsequently supported by structural analyses. However, Mycobacteria tuberculosis (Mtb) infection and Rhesus cytomegalovirus-vectored SIV vaccinations revealed contexts where HLA-E and the rhesus homologue, Mamu-E, presented diverse pathogen-derived peptides to CD8+ T cells, respectively. Here we present crystal structures of HLA-E in complex with HIV and Mtb-derived peptides. We show that despite the presence of preferred primary anchor residues, HLA-E-bound peptides can adopt alternative conformations within the peptide binding groove. Furthermore, combined structural and mutagenesis analyses illustrate a greater tolerance for hydrophobic and polar residues in the primary pockets than previously appreciated. Finally, biochemical studies reveal HLA-E peptide binding and exchange characteristics with potential relevance to its alternative antigen presenting function in vivo.

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

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s41467-018-05459-z.pdf

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