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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
Documents:
s41467-018-05459-z.pdf