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

Journal article

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

Authors: Whitehead, JD; Decool, H; Leyrat, C; Carrique, L; Fix, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 14
• Issue: 1
• Pages: 7627-7627
• Article number: 7627
• Publication date: 2023-11-22
• DOI: 10.1038/s41467-023-43434-5
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Transcription (linguistics); Biology; Chemistry; Respiratory tract infections; Human metapneumovirus; RNA-dependent RNA polymerase; Genetics; Molecular biology; RNA polymerase; Polymerase; Cell biology; RNA; Gene; Small nuclear RNA