Towards a structural understanding of RNA synthesis by negative strand RNA viral polymerases

• Published in: Current opinion in structural biology Vol. 36; pp. 75 - 84
• Main Authors: Reguera, Juan, Gerlach, Piotr, Cusack, Stephen
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2016
• Subjects: Binding Sites; DNA-Directed RNA Polymerases - chemistry; DNA-Directed RNA Polymerases - metabolism; Ebola virus; Genome, Viral; Models, Molecular; Nucleic Acid Conformation; Orthobunyavirus; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; RNA Caps; RNA Viruses - genetics; RNA Viruses - metabolism; RNA, Viral - biosynthesis; RNA, Viral - chemistry; RNA, Viral - genetics; Structure-Activity Relationship; Transcription, Genetic; Vesicular stomatitis virus; Virus Replication
• ISSN: 0959-440X; 1879-033X
• DOI: 10.1016/j.sbi.2016.01.002

•Crystal and cryo-EM structures of NSV polymerases influenza, La Crosse and VSV.•Segmented and non-segmented NSV polymerases have a similar extended core architecture.•Influenza and LACV structures show how the vRNA promoter is bound.•The cap-snatching mechanism of influenza polymerase (sNSV) is explained.•VSV (nsNSV) capping domains block product exit and thus need to rearrange.•Separate exit channels for template and product allow replication within the RNP context. Negative strand RNA viruses (NSVs), which may have segmented (sNSV) or non-segmented genomes (nsNSV) are responsible for numerous serious human infections such as Influenza, Measles, Rabies, Ebola, Crimean Congo Haemorrhagic Fever and Lassa Fever. Their RNA-dependent RNA polymerases transcribe and replicate the nucleoprotein coated viral genome within the context of a ribonucleoprotein particle. We review the first high resolution crystal and cryo-EM structures of representative NSV polymerases. The heterotrimeric Influenza and single-chain La Crosse orthobunyavirus polymerase structures (sNSV) show how specific recognition of both genome ends is achieved and is required for polymerase activation and how the sNSV specific ‘cap-snatching’ mechanism of transcription priming works. Vesicular Stomatitis Virus (nsNSV) polymerase shows a similar core architecture but has different flexibly linked C-terminal domains which perform mRNA cap synthesis. These structures pave the way for a more complete understanding of these complex, multifunctional machines which are also targets for anti-viral drug design.