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Characterization of interactions between hepatitis C virus NS5B polymerase, annexin A2 and RNA - effects on NS5B catalysis and allosteric inhibition
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
University of Bergen, Department of Biomedicine.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0003-2728-0340
2017 (English)In: Virology Journal, ISSN 1743-422X, E-ISSN 1743-422X, Vol. 14, article id 236Article in journal (Refereed) Published
Abstract [en]

Background: Direct acting antivirals (DAAs) provide efficient hepatitis C virus (HCV) therapy and clearance for a majority of patients, but are not available or effective for all patients. They risk developing HCV-induced hepatocellular carcinoma (HCC), for which the mechanism remains obscure and therapy is missing. Annexin A2 (AnxA2) has been reported to co-precipitate with the non-structural (NS) HCV proteins NS5B and NS3/NS4A, indicating a role in HCC tumorigenesis and effect on DAA therapy.

Methods: Surface plasmon resonance biosensor technology was used to characterize direct interactions between AnxA2 and HCV NS5B, NS3/NS4 and RNA, and the subsequent effects on catalysis and inhibition.

Results: No direct interaction between AnxA2 and NS3/NS4A was detected, while AnxA2 formed a slowly dissociating, high affinity (K D = 30 nM), complex with NS5B, decreasing its catalytic activity and affinity for the allosteric inhibitor filibuvir. The RNA binding of the two proteins was independent and AnxA2 and NS5B interacted with different RNAs in ternary complexes of AnxA2:NS5B:RNA, indicating specific preferences.

Conclusions: The complex interplay revealed between NS5B, AnxA2, RNA and filibuvir, suggests that AnxA2 may have an important role for the progression and treatment of HCV infections and the development of HCC, which should be considered also when designing new allosteric inhibitors.

Place, publisher, year, edition, pages
2017. Vol. 14, article id 236
Keywords [en]
Hepatitis C virus, NS5B, Annexin A2, RNA, allosteric inhibition, filibuvir, surface, plasmon resonance, Hepatocellular carcinoma
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-337575DOI: 10.1186/s12985-017-0904-4ISI: 000417867100001PubMedID: 29228983OAI: oai:DiVA.org:uu-337575DiVA, id: diva2:1170189
Funder
Swedish Research Council, D0571301Carl Tryggers foundation Available from: 2018-01-02 Created: 2018-01-02 Last updated: 2018-03-02Bibliographically approved

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Solbak, Sara M.Ø.Abdurakhmanov, EldarDanielson, U. Helena

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