Dataset Information

Crystal structure of the C-terminal 2',5'-phosphodiesterase domain of group A rotavirus protein VP3.

ABSTRACT: In response to viral infections, the mammalian innate immune system induces the production of the second messenger 2'-5' oligoadenylate (2-5A) to activate latent ribonuclease L (RNase L) that restricts viral replication and promotes apoptosis. A subset of rotaviruses and coronaviruses encode 2',5'-phosphodiesterase enzymes that hydrolyze 2-5A, thereby inhibiting RNase L activation. We report the crystal structure of the 2',5'-phosphodiesterase domain of group A rotavirus protein VP3 at 1.39 Å resolution. The structure exhibits a 2H phosphoesterase fold and reveals conserved active site residues, providing insights into the mechanism of 2-5A degradation in viral evasion of host innate immunity.

SUBMITTER: Brandmann T

PROVIDER: S-EPMC5068548 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Crystal structure of the C-terminal 2',5'-phosphodiesterase domain of group A rotavirus protein VP3.

Brandmann Tobias T Jinek Martin M

Proteins 20150325 5

In response to viral infections, the mammalian innate immune system induces the production of the second messenger 2'-5' oligoadenylate (2-5A) to activate latent ribonuclease L (RNase L) that restricts viral replication and promotes apoptosis. A subset of rotaviruses and coronaviruses encode 2',5'-phosphodiesterase enzymes that hydrolyze 2-5A, thereby inhibiting RNase L activation. We report the crystal structure of the 2',5'-phosphodiesterase domain of group A rotavirus protein VP3 at 1.39 Å re ...[more]

PMID: 25758703

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Project description:UnlabelledRotaviruses and orbiviruses are nonturreted Reoviridae members. The rotavirus VP3 protein is a multifunctional capping enzyme and antagonist of the interferon-induced cellular oligoadenylate synthetase-RNase L pathway. Despite mediating important processes, VP3 is the sole protein component of the rotavirus virion whose structure remains unknown. In the current study, we used sequence alignment and homology modeling to identify features common to nonturreted Reoviridae capping enzymes and to predict the domain organization, structure, and active sites of rotavirus VP3. Our results suggest that orbivirus and rotavirus capping enzymes share a domain arrangement similar to that of the bluetongue virus capping enzyme. Sequence alignments revealed conserved motifs and suggested that rotavirus and orbivirus capping enzymes contain a variable N-terminal domain, a central guanine-N7-methyltransferase domain that contains an additional inserted domain, and a C-terminal guanylyltransferase and RNA 5'-triphosphatase domain. Sequence conservation and homology modeling suggested that the insertion in the guanine-N7-methyltransferase domain is a ribose-2'-O-methyltransferase domain for most rotavirus species. Our analyses permitted putative identification of rotavirus VP3 active-site residues, including those that form the ribose-2'-O-methyltransferase catalytic tetrad, interact with S-adenosyl-l-methionine, and contribute to autoguanylation. Previous reports have indicated that group A rotavirus VP3 contains a C-terminal 2H-phosphodiesterase domain that can cleave 2'-5' oligoadenylates, thereby preventing RNase L activation. Our results suggest that a C-terminal phosphodiesterase domain is present in the capping enzymes from two additional rotavirus species. Together, these findings provide insight into a poorly understood area of rotavirus biology and are a springboard for future biochemical and structural studies of VP3.ImportanceRotaviruses are an important cause of severe diarrheal disease. The rotavirus VP3 protein caps viral mRNAs and helps combat cellular innate antiviral defenses, but little is known about its structure or enzymatic mechanisms. In this study, we used sequence- and structure-based alignments with related proteins to predict the structure of VP3 and identify enzymatic domains and active sites therein. This work provides insight into the mechanisms of rotavirus transcription and evasion of host innate immune defenses. An improved understanding of these processes may aid our ability to develop rotavirus vaccines and therapeutics.

Dataset Information

Crystal structure of the C-terminal 2',5'-phosphodiesterase domain of group A rotavirus protein VP3.

Publications

Crystal structure of the C-terminal 2',5'-phosphodiesterase domain of group A rotavirus protein VP3.

Similar Datasets

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