2. Academic Validation
  3. Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding

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

  • Nat Commun. 2018 Aug 7;9(1):3137. doi: 10.1038/s41467-018-05459-z.
Lucy C Walters 1,  Karl Harlos 2,  Simon Brackenridge 1,  Daniel Rozbesky 2,  Jordan R Barrett 1,  Vitul Jain 2,  Thomas S Walter 2,  Chris A O'Callaghan 3,  Persephone Borrow 1,  Mireille Toebes 4,  Scott G Hansen 5,  Jonah B Sacha 5,  Shaheed Abdulhaqq 5,  Justin M Greene 5,  Klaus Früh 5,  Emily Marshall 5,  Louis J Picker 5,  E Yvonne Jones 2,  Andrew J McMichael 6,  Geraldine M Gillespie 7
Affiliations

Affiliations

  • 1 Nuffield Department of Medicine Research Building, Roosevelt Drive, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK.
  • 2 Division of Structural Biology, Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, UK.
  • 3 Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, OX3 7BN, UK.
  • 4 Department Molecular Oncology and Immunology, B6 Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands.
  • 5 Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA.
  • 6 Nuffield Department of Medicine Research Building, Roosevelt Drive, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK. [email protected].
  • 7 Nuffield Department of Medicine Research Building, Roosevelt Drive, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK. [email protected].
PMID: 30087334 DOI: 10.1038/s41467-018-05459-z
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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