Structure of a paramyxovirus polymerase complex reveals a unique methyltransferase-CTD conformation

Ryan Abdella, Megha Aggarwal, Takashi Okura, Robert A. Lamb*, Yuan He

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Paramyxoviruses are enveloped, nonsegmented, negative-strand RNA viruses that cause a wide spectrum of human and animal diseases. The viral genome, packaged by the nucleoprotein (N), serves as a template for the polymerase complex, composed of the large protein (L) and the homo-tetrameric phosphoprotein (P). The ∼250-kDa L possesses all enzymatic activities necessary for its function but requires P in vivo. Structural information is available for individual P domains from different paramyxoviruses, but how P interacts with L and how that affects the activity of L is largely unknown due to the lack of high-resolution structures of this complex in this viral family. In this study we determined the structure of the L-P complex from parainfluenza virus 5 (PIV5) at 4.3-Å resolution using cryoelectron microscopy, as well as the oligomerization domain (OD) of P at 1.4-Å resolution using X-ray crystallography. POD associates with the RNA-dependent RNA polymerase domain of L and protrudes away from it, while the X domain of one chain of P is bound near the L nucleotide entry site. The methyltransferase (MTase) domain and the C-terminal domain (CTD) of L adopt a unique conformation, positioning the MTase active site immediately above the poly-ribonucleotidyltransferase domain and near the likely exit site for the product RNA 5′ end. Our study reveals a potential mechanism that mononegavirus polymerases may employ to switch between transcription and genome replication. This knowledge will assist in the design and development of antivirals against paramyxoviruses.

Original languageEnglish (US)
Pages (from-to)4931-4941
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number9
DOIs
StatePublished - Mar 3 2020

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Keywords

  • Cryo-EM
  • Paramyxovirus
  • Polymerase
  • Replication
  • Transcription

ASJC Scopus subject areas

  • General

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