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Cyclophilin A interacts with domain II of hepatitis C virus NS5A and stimulates RNA binding in an isomerase-dependent manner

Foster, Toshana L.; Gallay, Philippe; Stonehouse, Nicola J.; Harris, Mark

Authors

Philippe Gallay

Nicola J. Stonehouse

Mark Harris



Abstract

NS5A plays a critical, yet poorly defined, role in hepatitis C virus genome replication. The protein consists of three domains, each of which is able to bind independently to the 3′ untranslated region (UTR) of the viral positive strand genomic RNA. The peptidyl-prolyl isomerase cyclophilin A (CypA) binds to domain II, catalyzing cis-trans isomerization. CypA inhibitors such as cyclosporine (CsA) have been shown to inhibit hepatitis C virus (HCV) replication. We show here that CypA stimulated domain II RNA binding activity, and this stimulation was abrogated by CsA. An isomerase mutant of CypA (H126Q) failed to bind to domain II and did not stimulate RNA binding. Finally, we demonstrate that the RNA binding of two domain II mutants, the D316E and D316E/Y317N mutants, previously shown to exhibit CypA independence for RNA replication, was unaffected by CypA. This study provides an insight into the molecular mechanism of CypA activity during HCV replication and further validates the use of CypA inhibitors in HCV therapy.

Citation

Foster, T. L., Gallay, P., Stonehouse, N. J., & Harris, M. (2011). Cyclophilin A interacts with domain II of hepatitis C virus NS5A and stimulates RNA binding in an isomerase-dependent manner. Journal of Virology, 85(14), 7460-7464. https://doi.org/10.1128/jvi.00393-11

Journal Article Type Article
Acceptance Date May 4, 2011
Online Publication Date May 18, 2011
Publication Date Jul 15, 2011
Deposit Date Mar 21, 2019
Journal Journal of Virology
Print ISSN 0022-538X
Publisher American Society for Microbiology
Peer Reviewed Peer Reviewed
Volume 85
Issue 14
Pages 7460-7464
DOI https://doi.org/10.1128/jvi.00393-11
Keywords Immunology; Insect Science; Microbiology; Virology
Public URL https://nottingham-repository.worktribe.com/output/1673835
Publisher URL https://jvi.asm.org/content/85/14/7460