Structure of the N-RNA/P interface indicates mode of L/P recruitment to the nucleocapsid of human metapneumovirusVisa övriga samt affilieringar
2023 (Engelska)Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikel-id 7627Artikel i tidskrift (Refereegranskat) Published
Abstract [en]
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.
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Springer Nature, 2023. Vol. 14, nr 1, artikel-id 7627
Nationell ämneskategori
Biokemi och molekylärbiologi Cell- och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-217549DOI: 10.1038/s41467-023-43434-5PubMedID: 37993464Scopus ID: 2-s2.0-85177975232OAI: oai:DiVA.org:umu-217549DiVA, id: diva2:1818900
2023-12-122023-12-122023-12-14Bibliografiskt granskad