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Structure of the N-RNA/P interface indicates mode of L/P recruitment to the nucleocapsid of human metapneumovirus

Author

Listed:
  • Jack D. Whitehead

    (University of Oxford
    University of Oxford)

  • Hortense Decool

    (Université Paris-Saclay, INRAE, UVSQ, VIM)

  • Cédric Leyrat

    (Université de Montpellier, CNRS, INSERM)

  • Loic Carrique

    (University of Oxford)

  • Jenna Fix

    (Université Paris-Saclay, INRAE, UVSQ, VIM)

  • Jean-François Eléouët

    (Université Paris-Saclay, INRAE, UVSQ, VIM)

  • Marie Galloux

    (Université Paris-Saclay, INRAE, UVSQ, VIM)

  • Max Renner

    (Umeå University
    Umeå University)

Abstract

Human metapneumovirus (HMPV) is a major cause of respiratory illness in young children. The HMPV polymerase (L) binds an obligate cofactor, the phosphoprotein (P). During replication and transcription, the L/P complex traverses the viral RNA genome, which is encapsidated within nucleoproteins (N). An essential interaction between N and a C-terminal region of P tethers the L/P polymerase to the template. This N-P interaction is also involved in the formation of cytoplasmic viral factories in infected cells, called inclusion bodies. To define how the polymerase component P recognizes N-encapsidated RNA (N-RNA) we employed cryogenic electron microscopy (cryo-EM) and molecular dynamics simulations, coupled to activity assays and imaging of inclusion bodies in cells. We report a 2.9 Å resolution structure of a triple-complex between multimeric N, bound to both RNA and the C-terminal region of P. Furthermore, we also present cryo-EM structures of assembled N in different oligomeric states, highlighting the plasticity of N. Combined with our functional assays, these structural data delineate in molecular detail how P attaches to N-RNA whilst retaining substantial conformational dynamics. Moreover, the N-RNA-P triple complex structure provides a molecular blueprint for the design of therapeutics to potentially disrupt the attachment of L/P to its template.

Suggested Citation

  • Jack D. Whitehead & Hortense Decool & Cédric Leyrat & Loic Carrique & Jenna Fix & Jean-François Eléouët & Marie Galloux & Max Renner, 2023. "Structure of the N-RNA/P interface indicates mode of L/P recruitment to the nucleocapsid of human metapneumovirus," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43434-5
    DOI: 10.1038/s41467-023-43434-5
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