Identification of a Small Interface Between the Methyltransferase and RNA Polymerase of NS5 That is Essential for Zika Virus Replication

Overview

Journal Sci Rep

Specialty Science

Date 2018 Nov 28

PMID 30478404

Citations 4

Authors

Timur Rusanov

Tatiana Kent

Mohsan Saeed

Trung M Hoang

Crystal Thomas

Charles M Rice

Richard T Pomerantz

Affiliations

Soon will be listed here.

Abstract

The spread of Zika virus (ZIKV) has caused an international health emergency due to its ability to cause microcephaly in infants. Yet, our knowledge of how ZIKV replicates at the molecular level is limited. For example, how the non-structural protein 5 (NS5) performs replication, and in particular whether the N-terminal methytransferase (MTase) domain is essential for the function of the C-terminal RNA-dependent RNA polymerase (RdRp) remains unclear. In contrast to previous reports, we find that MTase is absolutely essential for all activities of RdRp in vitro. For instance, the MTase domain confers stability onto the RdRp elongation complex (EC) and and is required for de novo RNA synthesis and nucleotide incorporation by RdRp. Finally, structure function analyses identify key conserved residues at the MTase-RdRp interface that specifically activate RdRp elongation and are essential for ZIKV replication in Huh-7.5 cells. These data demonstrate the requirement for the MTase-RdRp interface in ZIKV replication and identify a specific site within this region as a potential site for therapeutic development.

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