Dataset Information

Energetics of Preferential Binding of Retinoic Acid-Inducible Gene-I to Double-Stranded Viral RNAs with 5' Tri-/Diphosphate over 5' Monophosphate.

ABSTRACT: Retinoic acid-inducible gene-I (RIG-I) is a cytosolic sensor protein that recognizes viral RNAs and triggers an innate immune response in cells. Panhandle-like base-paired blunt-ended 5' ppp/pp-dsRNA is a characteristic feature of viral RNAs. Structural studies of RIG-I C-terminal domain bound 5' ppp/pp-dsRNA complexes show the direct interaction between all the 5' terminal phosphates (?, ?, and ?) and protein, suggesting ? phosphate might be a major recognition determinant for RIG-I binding. Biochemical studies, however, suggest that 5' pp-dsRNA is the minimal determinant for RIG-I binding and antiviral response. Despite biochemical and structural studies, the origin of viral RNA recognition by RIG-I is an unsolved problem. X-ray structures of RIG-I bound dsRNA not only provide atomic insight into the interaction network but also provide sufficiently good models for computational studies. We report structure-based molecular dynamics (MD) free energy calculations to quantitatively estimate the energetics of RIG-I binding to dsRNA containing 5' ppp, 5' pp, and 5' p. The results suggest that RIG-I weakly discriminates between 5' ppp-dsRNA and 5' pp-dsRNA (favoring former) and strongly disfavors 5' p-dsRNA with respect to the rest. Interestingly, direct interaction between ? phosphate of 5' ppp-dsRNA and RIG-I is a robust feature of the MD simulations. dsRNA binding to RIG-I is associated with Mg2+ dissociation from the 5' phosphate/s of dsRNA. The higher Mg2+ dissociation penalty from 5' ppp-dsRNA with respect to 5' pp-dsRNA offsets most of the favorable interaction between RIG-I and ? phosphate of 5' ppp-dsRNA. This leads to weak discrimination between 5' ppp-dsRNA and 5' pp-dsRNA. 5' p-dsRNA is discriminated strongly because of the loss of interaction with RIG-I.

SUBMITTER: Kumar A

PROVIDER: S-EPMC6044841 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Publications

Energetics of Preferential Binding of Retinoic Acid-Inducible Gene-I to Double-Stranded Viral RNAs with 5' Tri-/Diphosphate over 5' Monophosphate.

Kumar Amit A Satpati Priyadarshi P

ACS omega 20180403 4

Retinoic acid-inducible gene-I (RIG-I) is a cytosolic sensor protein that recognizes viral RNAs and triggers an innate immune response in cells. Panhandle-like base-paired blunt-ended 5' ppp/pp-dsRNA is a characteristic feature of viral RNAs. Structural studies of RIG-I C-terminal domain bound 5' ppp/pp-dsRNA complexes show the direct interaction between all the 5' terminal phosphates (α, β, and γ) and protein, suggesting γ phosphate might be a major recognition determinant for RIG-I binding. Bi ...[more]

PMID: 30023880

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Project description:In plants, the biosynthesis of isopentenyl diphosphate, the central precursor of all isoprenoids, proceeds via two separate pathways. The cytosolic compartment harbors the mevalonate pathway, whereas the newly discovered deoxyxylulose 5-phosphate pathway, which also operates in certain eubacteria, including Escherichia coli, is localized to plastids. Only the first two steps of the plastidial pathway, which involve the condensation of pyruvate and glyceraldehyde 3-phosphate to deoxyxylulose 5-phosphate followed by intramolecular rearrangement and reduction to 2-C-methylerythritol 4-phosphate, have been established. Here we report the cloning from peppermint (Mentha x piperita) and E. coli, and expression, of a kinase that catalyzes the phosphorylation of isopentenyl monophosphate as the last step of this biosynthetic sequence to isopentenyl diphosphate. The plant gene defines an ORF of 1,218 bp that, when the proposed plastidial targeting sequence is excluded, corresponds to approximately 308 aa with a mature size of approximately 33 kDa. The E. coli gene (ychB), which is located at 27.2 min of the chromosomal map, consists of 852 nt, encoding a deduced enzyme of 283 aa with a size of 31 kDa. These enzymes represent a conserved class of the GHMP family of kinases, which includes galactokinase, homoserine kinase, mevalonate kinase, and phosphomevalonate kinase, with homologues in plants and several eubacteria. Besides the preferred substrate isopentenyl monophosphate, the recombinant peppermint and E. coli kinases also phosphorylate isopentenol, and, much less efficiently, dimethylallyl alcohol, but dimethylallyl monophosphate does not serve as a substrate. Incubation of secretory cells isolated from peppermint glandular trichomes with isopentenyl monophosphate resulted in the rapid production of monoterpenes and sesquiterpenes, confirming that isopentenyl monophosphate is the physiologically relevant, terminal intermediate of the deoxyxylulose 5-phosphate pathway.

Dataset Information

Energetics of Preferential Binding of Retinoic Acid-Inducible Gene-I to Double-Stranded Viral RNAs with 5' Tri-/Diphosphate over 5' Monophosphate.

Publications

Energetics of Preferential Binding of Retinoic Acid-Inducible Gene-I to Double-Stranded Viral RNAs with 5' Tri-/Diphosphate over 5' Monophosphate.

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