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Relationships among the positive strand and double-strand RNA viruses as viewed through their RNA-dependent RNA polymerases.

ABSTRACT: The sequences of 50 RNA-dependent RNA polymerases (RDRPs) from 43 positive strand and 7 double strand RNA (dsRNA) viruses have been compared. The alignment permitted calculation of distances among the 50 viruses and a resultant dendrogram based on every amino acid, rather than just those amino acids in the conserved motifs. Remarkably, a large subgroup of these viruses, including vertebrate, plant, and insect viruses, forms a single cluster whose only common characteristic is exploitation of insect hosts or vectors. This similarity may be due to molecular constraints associated with a present and/or past ability to infect insects and/or to common descent from insect viruses. If common descent is important, as it appears to be, all the positive strand RNA viruses of eucaryotes except for the picornaviruses may have evolved from an ancestral dsRNA virus. Viral RDRPs appear to be inherited as modules rather than as portions of single RNA segments, implying that RNA recombination has played an important role in their dissemination.

SUBMITTER: Bruenn JA

PROVIDER: S-EPMC333583 | biostudies-other | 1991 Jan

REPOSITORIES: biostudies-other

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Relationships among the positive strand and double-strand RNA viruses as viewed through their RNA-dependent RNA polymerases.

Bruenn J A JA

Nucleic acids research 19910101 2

The sequences of 50 RNA-dependent RNA polymerases (RDRPs) from 43 positive strand and 7 double strand RNA (dsRNA) viruses have been compared. The alignment permitted calculation of distances among the 50 viruses and a resultant dendrogram based on every amino acid, rather than just those amino acids in the conserved motifs. Remarkably, a large subgroup of these viruses, including vertebrate, plant, and insect viruses, forms a single cluster whose only common characteristic is exploitation of ins ...[more]

PMID: 2014162

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Project description:The RNA-dependent RNA polymerases (RdRPs) encoded by the RNA viruses are a unique class of nucleic acid polymerases. Each viral RdRP contains a 500-600 residue catalytic module with palm, fingers, and thumb domains forming an encircled human right hand architecture. Seven polymerase catalytic motifs are located in the RdRP palm and fingers domains, comprising the most conserved parts of the RdRP and are responsible for the RNA-only specificity in catalysis. Functional regions are often found fused to the RdRP catalytic module, resulting in a high level of diversity in RdRP global structure and regulatory mechanism. In this review, we surveyed all 46 RdRP-sequence available virus families of the positive-strand RNA viruses listed in the 2018b collection of the International Committee on Virus Taxonomy (ICTV) and chose a total of 49 RdRPs as representatives. By locating hallmark residues in RdRP catalytic motifs and by referencing structural and functional information in the literature, we were able to estimate the N- and C-terminal boundaries of the catalytic module in these RdRPs, which in turn serve as reference points to predict additional functional regions beyond the catalytic module. Interestingly, a large number of virus families may have additional regions fused to the RdRP N-terminus, while only a few of them have such regions on the C-terminal side of the RdRP. The current knowledge on these additional regions, either in three-dimensional (3D) structure or in function, is quite limited. In the five RdRP-structure available virus families in the positive-strand RNA viruses, only the Flaviviridae family has the 3D structural information resolved for such regions. Hence, future efforts to solve full-length RdRP structures containing these regions and to dissect the functional contribution of them are necessary to improve the overall understanding of the RdRP proteins as an evolutionarily integrated group, and our analyses here may serve as a guideline for selecting representative RdRP systems in these studies.

Project description:UnlabelledViral RNA-dependent RNA polymerases are considered to be low-fidelity enzymes, providing high mutation rates that allow for the rapid adaptation of RNA viruses to different host cell environments. Fidelity is tuned to provide the proper balance of virus replication rates, pathogenesis, and tissue tropism needed for virus growth. Using our structures of picornaviral polymerase-RNA elongation complexes, we have previously engineered more than a dozen coxsackievirus B3 polymerase mutations that significantly altered virus replication rates and in vivo fidelity and also provided a set of secondary adaptation mutations after tissue culture passage. Here we report a biochemical analysis of these mutations based on rapid stopped-flow kinetics to determine elongation rates and nucleotide discrimination factors. The data show a spatial separation of fidelity and replication rate effects within the polymerase structure. Mutations in the palm domain have the greatest effects on in vitro nucleotide discrimination, and these effects are strongly correlated with elongation rates and in vivo mutation frequencies, with faster polymerases having lower fidelity. Mutations located at the top of the finger domain, on the other hand, primarily affect elongation rates and have relatively minor effects on fidelity. Similar modulation effects are seen in poliovirus polymerase, an inherently lower-fidelity enzyme where analogous mutations increase nucleotide discrimination. These findings further our understanding of viral RNA-dependent RNA polymerase structure-function relationships and suggest that positive-strand RNA viruses retain a unique palm domain-based active-site closure mechanism to fine-tune replication fidelity.ImportancePositive-strand RNA viruses represent a major class of human and animal pathogens with significant health and economic impacts. These viruses replicate by using a virally encoded RNA-dependent RNA polymerase enzyme that has low fidelity, generating many mutations that allow the rapid adaptation of these viruses to different tissue types and host cells. In this work, we use a structure-based approach to engineer mutations in viral polymerases and study their effects on in vitro nucleotide discrimination as well as virus growth and genome replication fidelity. These results show that mutation rates can be drastically increased or decreased as a result of single mutations at several key residues in the polymerase palm domain, and this can significantly attenuate virus growth in vivo. These findings provide a pathway for developing live attenuated virus vaccines based on engineering the polymerase to reduce virus fitness.

Dataset Information

Relationships among the positive strand and double-strand RNA viruses as viewed through their RNA-dependent RNA polymerases.

Publications

Relationships among the positive strand and double-strand RNA viruses as viewed through their RNA-dependent RNA polymerases.

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