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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 , 2018. "Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05459-z
    DOI: 10.1038/s41467-018-05459-z
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    Cited by:

    1. Brooke D. Huisman & Ning Guan & Timo Rückert & Lee Garner & Nishant K. Singh & Andrew J. McMichael & Geraldine M. Gillespie & Chiara Romagnani & Michael E. Birnbaum, 2023. "High-throughput characterization of HLA-E-presented CD94/NKG2x ligands reveals peptides which modulate NK cell activation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Andrew Gibson & Ramesh Ram & Rama Gangula & Yueran Li & Eric Mukherjee & Amy M. Palubinsky & Chelsea N. Campbell & Michael Thorne & Katherine C. Konvinse & Phuti Choshi & Pooja Deshpande & Sarah Pedre, 2024. "Multiomic single-cell sequencing defines tissue-specific responses in Stevens-Johnson syndrome and toxic epidermal necrolysis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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