Structure of a paramyxovirus polymerase complex reveals a unique methyltransferase-CTD conformation.
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. P-OD 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.
['Abdella|Ryan|R|0000-0002-6129-3244', 'Aggarwal|Megha|M|0000-0002-6989-9064', 'Okura|Takashi|T|', 'Lamb|Robert A|RA|', 'He|Yuan|Y|0000-0002-1455-3963']
D020134:Catalytic Domain D020285:Cryoelectron Microscopy D018360:Crystallography, X-Ray D016679:Genome, Viral D008780:Methyltransferases D008958:Models, Molecular D009698:Nucleoproteins D045402:Parainfluenza Virus 5 D018098:Paramyxovirinae D010750:Phosphoproteins D011485:Protein Binding D011487:Protein Conformation D000072417:Protein Domains D014764:Viral Proteins
paramyxovirus polymerase transcription replication Cryo-EM