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

Lucy C. Walters, Karl Harlos, Simon Brackenridge, Daniel Rozbesky, Jordan R. Barrett, Vitul Jain, Thomas S. Walter, Chris A. O’Callaghan, Persephone Borrow, Mireille Toebes, Scott G. Hansen, Jonah B Sacha, Shaheed Abdulhaqq, Justin M. Greene, Klaus Früh, Emily Marshall, Louis J. Picker, E. Yvonne Jones, Andrew J. McMichael () and Geraldine M. Gillespie ()
Additional contact information
Lucy C. Walters: University of Oxford
Karl Harlos: University of Oxford
Simon Brackenridge: University of Oxford
Daniel Rozbesky: University of Oxford
Jordan R. Barrett: University of Oxford
Vitul Jain: University of Oxford
Thomas S. Walter: University of Oxford
Chris A. O’Callaghan: University of Oxford
Persephone Borrow: University of Oxford
Mireille Toebes: B6 Plesmanlaan 121
Scott G. Hansen: Oregon Health & Science University
Jonah B 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: University of Oxford
Andrew J. McMichael: University of Oxford
Geraldine M. Gillespie: University of Oxford

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05459-z

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