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 Hansen, Jonah Sacha, Shaheed Abdulhaqq, Justin M. Greene, Klaus Frueh, Emily Marshall, Louis Picker, E. Yvonne Jones, Andrew J. McMichael, Geraldine M. Gillespie

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Article number3137
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

leukocytes
pathogens
antigens
Pathogens
HLA Antigens
Anchors
peptides
Epitopes
Peptides
tuberculosis
Mycobacterium tuberculosis
Mutagenesis
Mycobacterium Infections
T-cells
mutagenesis
human immunodeficiency virus
Major Histocompatibility Complex
Cytomegalovirus
Natural Killer Cells
infectious diseases

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Walters, L. C., Harlos, K., Brackenridge, S., Rozbesky, D., Barrett, J. R., Jain, V., ... Gillespie, G. M. (2018). Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding. Nature Communications, 9(1), [3137]. https://doi.org/10.1038/s41467-018-05459-z

Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding. / Walters, Lucy C.; Harlos, Karl; Brackenridge, Simon; Rozbesky, Daniel; Barrett, Jordan R.; Jain, Vitul; Walter, Thomas S.; O’Callaghan, Chris A.; Borrow, Persephone; Toebes, Mireille; Hansen, Scott; Sacha, Jonah; Abdulhaqq, Shaheed; Greene, Justin M.; Frueh, Klaus; Marshall, Emily; Picker, Louis; Jones, E. Yvonne; McMichael, Andrew J.; Gillespie, Geraldine M.

In: Nature Communications, Vol. 9, No. 1, 3137, 01.12.2018.

Research output: Contribution to journalArticle

Walters, LC, Harlos, K, Brackenridge, S, Rozbesky, D, Barrett, JR, Jain, V, Walter, TS, O’Callaghan, CA, Borrow, P, Toebes, M, Hansen, S, Sacha, J, Abdulhaqq, S, Greene, JM, Frueh, K, Marshall, E, Picker, L, Jones, EY, McMichael, AJ & Gillespie, GM 2018, 'Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding', Nature Communications, vol. 9, no. 1, 3137. https://doi.org/10.1038/s41467-018-05459-z
Walters, Lucy C. ; Harlos, Karl ; Brackenridge, Simon ; Rozbesky, Daniel ; Barrett, Jordan R. ; Jain, Vitul ; Walter, Thomas S. ; O’Callaghan, Chris A. ; Borrow, Persephone ; Toebes, Mireille ; Hansen, Scott ; Sacha, Jonah ; Abdulhaqq, Shaheed ; Greene, Justin M. ; Frueh, Klaus ; Marshall, Emily ; Picker, Louis ; Jones, E. Yvonne ; McMichael, Andrew J. ; Gillespie, Geraldine M. / Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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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.",
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