Structural insights into viral RNA capping and plasma membrane targeting by Chikungunya virus nonstructural protein 1

Zhang, Kuo; Law, Yee-Song; Law, Michelle Cheok Yien; Tan, Yen Nee; Wirawan, Melissa; Luo, Dahai

doi:10.1016/j.chom.2021.02.018

Cited by 51 publications

(88 citation statements)

References 56 publications

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“… Left column: the spherule RNA replication complexes of nodaviruses are crowned by 12-fold symmetric crown complex of protein A [ 27 •• ]. Middle column: In the absence of other viral proteins, exogenously expressed alphavirus nsP1, which contains RNA capping domains similar to those of the nodavirus crown basal region, assembles into a 12-mer ring that is proposed to reside atop alphavirus spherules similarly to the basal ring of the nodavirus crown [ 29 •• , 30 •• ]. In active alphavirus RNA replication complexes, this nsP1 ring presumably represents the base of a larger complex that also contains additional alphavirus RNA replication proteins nsPs 2–4 ( Figure 1 ).…”

Section: Parallels With Alphaviruses and Coronavirusesmentioning

confidence: 99%

Cryo-electron microscopy of nodavirus RNA replication organelles illuminates positive-strand RNA virus genome replication

Unchwaniwala

Zhan

Boon

et al. 2021

Current Opinion in Virology

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The nodavirus flock house virus recently provided a well-characterized model for the first cryo-electron microscope tomography of membrane-bound, positive-strand RNA ((+)RNA) virus genome replication complexes (RCs). The resulting first views of RC organization and complementary biochemical results showed that the viral RNA replication vesicle is tightly packed with the dsRNA genomic RNA replication intermediate, and that (+)ssRNA replication products are released through the vesicle neck to the cytosol through a 12-fold symmetric ring or crown of multi-functional viral RNA replication proteins, which likely also contribute to viral RNA synthesis. Subsequent studies identified similar crown-like RNA replication protein complexes in alphavirus and coronavirus RCs, indicating related mechanisms across highly divergent (+)RNA viruses. As outlined in this review, these results have significant implications for viral function, evolution and control.

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Section: Parallels With Alphaviruses and Coronavirusesmentioning

confidence: 99%

Cryo-electron microscopy of nodavirus RNA replication organelles illuminates positive-strand RNA virus genome replication

Unchwaniwala

Zhan

Boon

et al. 2021

Current Opinion in Virology

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“…In addition to its MTase activity, nsP1 also possesses a guanylyltransferase (GTase) activity that allows for the transfer of the m 7 GMP moiety to the viral RNA forming the cap-0 structure at the 5′ end [ 118 , 119 , 120 ]. The enzymatic activity of nsP1 is dependent on the binding of the protein to cellular membranes [ 119 , 121 , 122 ].…”

Section: Replication-induced Membrane Rearrangementsmentioning

confidence: 99%

“…The exact mechanism of how nsP1 binds to membranes remained elusive until the structure of the protein from CHIKV was recently solved. The structure revealed that twelve copies of nsP1 assemble to form an 18.6-nanometer ring structure with a 7–7.5-nanometer-wide inner channel that allows for the transfer of RNA molecules and small globular proteins [ 121 , 122 ]. NsP1 rings were enzymatically active, whereas monomeric nsP1 was inactive, indicating that the oligomerization of the protein is required for its enzymatic activity.…”

Section: Replication-induced Membrane Rearrangementsmentioning

confidence: 99%

“…These two loops intertwine via hand-in-hand inter-loop bonding, forming membrane-binding spikes and bringing together neighboring nsP1 molecules. This interaction is crucial for activating the enzyme by stabilizing the two catalytic domains essential for its function [ 121 , 122 ]. Together, the new structures of nsP1 highlight the importance of its membrane association and confirm that nsP1 forms the base for the assembly of the RC at the neck of replication spherules ( Figure 1 ).…”

Section: Replication-induced Membrane Rearrangementsmentioning

confidence: 99%

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Alphavirus-Induced Membrane Rearrangements during Replication, Assembly, and Budding

2021

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Alphaviruses are arthropod-borne viruses mainly transmitted by hematophagous insects that cause moderate to fatal disease in humans and other animals. Currently, there are no approved vaccines or antivirals to mitigate alphavirus infections. In this review, we summarize the current knowledge of alphavirus-induced structures and their functions in infected cells. Throughout their lifecycle, alphaviruses induce several structural modifications, including replication spherules, type I and type II cytopathic vacuoles, and filopodial extensions. Type I cytopathic vacuoles are replication-induced structures containing replication spherules that are sites of RNA replication on the endosomal and lysosomal limiting membrane. Type II cytopathic vacuoles are assembly induced structures that originate from the Golgi apparatus. Filopodial extensions are induced at the plasma membrane and are involved in budding and cell-to-cell transport of virions. This review provides an overview of the viral and host factors involved in the biogenesis and function of these virus-induced structures. Understanding virus–host interactions in infected cells will lead to the identification of new targets for antiviral discovery.

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“…In contrast, structural information for nsP4 has been lacking, in large part due to its intrinsic flexibility, which is important for its biological functions (15)(16)(17)(18)(19)(20)(21)(22)(23). Out of a total of ~610 amino acid residues, the 109 N-terminal residues of nsP4 comprise a functionally poorly defined N-terminal domain (NTD) unique to alphaviruses.…”

Section: Main Text Introductionmentioning

confidence: 99%

Crystal structures of alphavirus nonstructural protein 4 (nsP4) reveal an intrinsically dynamic RNA-dependent RNA polymerase fold

Tan

Liu

et al. 2021

Preprint

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Alphaviruses such as Ross River virus (RRV), chikungunya virus and Venezuelan equine encephalitis virus are mosquito-borne pathogens that can cause arthritis or encephalitis diseases. Nonstructural protein 4 (nsP4) of alphaviruses possesses RNA-dependent RNA polymerase (RdRp) activity essential for viral RNA replication. No 3D structure has been available for nsP4 of any alphaviruses despite its importance for understanding alphaviral RNA replication and for the design of antiviral drugs. Here, we report a crystal structure of the RdRp domain of nsP4 from RRV determined at a resolution of 2.6 Å. The structure of the alphavirus RdRp domain appears most closely related to RdRps from pestiviruses, noroviruses and picornaviruses. Using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and nuclear magnetic resonance (NMR) methods, we showed that in-solution nsP4 is highly dynamic with an intrinsically disordered N-terminal domain. Both full-length nsP4 and the RdRp domain were able to catalyze in vitro RNA polymerization. Structure-guided mutagenesis using a trans-replicase system identified nsP4 regions critical for viral RNA replication.

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Structural insights into viral RNA capping and plasma membrane targeting by Chikungunya virus nonstructural protein 1

Cited by 51 publications

References 56 publications

Cryo-electron microscopy of nodavirus RNA replication organelles illuminates positive-strand RNA virus genome replication

Cryo-electron microscopy of nodavirus RNA replication organelles illuminates positive-strand RNA virus genome replication

Alphavirus-Induced Membrane Rearrangements during Replication, Assembly, and Budding

Crystal structures of alphavirus nonstructural protein 4 (nsP4) reveal an intrinsically dynamic RNA-dependent RNA polymerase fold

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