A locking mechanism regulates RNA synthesis and host protein interaction by the hepatitis C virus polymerase

Sreedhar Chinnaswamy, Ian Yarbrough, Satheesh Palaninathan, C. T Ranjith Kumar, Vinodhini Vijayaraghavan, Borries Demeler, Stanley M. Lemon, James C. Sacchettini, C. Cheng Kao

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Mutational analysis of the hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) template channel identified two residues, Trp397 and His428, which are required for de novo initiation but not for extension from a primer. These two residues interact with the Δ1 loop on the surface of the RdRp. A deletion within the Δ1 loop also resulted in comparable activities. The mutant proteins exhibit increased double-stranded RNA binding compared with the wild type, suggesting that the Δ1 loop serves as a flexible locking mechanism to regulate the conformations needed for de novo initiation and for elongative RNA synthesis. A similar locking motif can be found in other viral RdRps. Products associated with the open conformation of the HCV RdRp were inhibited by interaction with the retinoblastoma protein but not cyclophilin A. Different conformations of the HCV RdRp can thus affect RNA synthesis and interaction with cellular proteins.

Original languageEnglish (US)
Pages (from-to)20535-20546
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number29
DOIs
StatePublished - Jul 18 2008

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RNA Replicase
Viruses
Hepacivirus
RNA
Conformations
Proteins
Cyclophilin A
Retinoblastoma Protein
Double-Stranded RNA
Mutant Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Chinnaswamy, S., Yarbrough, I., Palaninathan, S., Kumar, C. T. R., Vijayaraghavan, V., Demeler, B., ... Kao, C. C. (2008). A locking mechanism regulates RNA synthesis and host protein interaction by the hepatitis C virus polymerase. Journal of Biological Chemistry, 283(29), 20535-20546. https://doi.org/10.1074/jbc.M801490200

A locking mechanism regulates RNA synthesis and host protein interaction by the hepatitis C virus polymerase. / Chinnaswamy, Sreedhar; Yarbrough, Ian; Palaninathan, Satheesh; Kumar, C. T Ranjith; Vijayaraghavan, Vinodhini; Demeler, Borries; Lemon, Stanley M.; Sacchettini, James C.; Kao, C. Cheng.

In: Journal of Biological Chemistry, Vol. 283, No. 29, 18.07.2008, p. 20535-20546.

Research output: Contribution to journalArticle

Chinnaswamy, S, Yarbrough, I, Palaninathan, S, Kumar, CTR, Vijayaraghavan, V, Demeler, B, Lemon, SM, Sacchettini, JC & Kao, CC 2008, 'A locking mechanism regulates RNA synthesis and host protein interaction by the hepatitis C virus polymerase', Journal of Biological Chemistry, vol. 283, no. 29, pp. 20535-20546. https://doi.org/10.1074/jbc.M801490200
Chinnaswamy S, Yarbrough I, Palaninathan S, Kumar CTR, Vijayaraghavan V, Demeler B et al. A locking mechanism regulates RNA synthesis and host protein interaction by the hepatitis C virus polymerase. Journal of Biological Chemistry. 2008 Jul 18;283(29):20535-20546. https://doi.org/10.1074/jbc.M801490200
Chinnaswamy, Sreedhar ; Yarbrough, Ian ; Palaninathan, Satheesh ; Kumar, C. T Ranjith ; Vijayaraghavan, Vinodhini ; Demeler, Borries ; Lemon, Stanley M. ; Sacchettini, James C. ; Kao, C. Cheng. / A locking mechanism regulates RNA synthesis and host protein interaction by the hepatitis C virus polymerase. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 29. pp. 20535-20546.
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