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

Jack D. Whitehead, Hortense Decool, Cédric Leyrat, Loic Carrique, Jenna Fix, Jean-François Eléouët, Marie Galloux () and Max Renner ()
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Jack D. Whitehead: 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

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43434-5

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