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Conserved glycine 33 residue in flexible domain I of hepatitis C virus core protein is critical for virus infectivity

Angus, Allan G. N. and Loquet, Antoine and Stack, Séamus J. and Dalrymple, David and Gatherer, Derek and Penin, François and Patel, Arvind H. (2012) Conserved glycine 33 residue in flexible domain I of hepatitis C virus core protein is critical for virus infectivity. Journal of Virology, 86 (2). pp. 679-690. ISSN 0022-538X

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Abstract

Hepatitis C virus core protein forms the viral nucleocapsid and plays a critical role in the formation of infectious particles. In this study, we demonstrate that the highly conserved residue G33, located within domain 1 of the core protein, is important for the production of cell culture-infectious virus (HCVcc). Alanine substitution at this position in the JFH1 genome did not alter viral RNA replication but reduced infectivity by ∼2 logs. Virus production by this core mutant could be rescued by compensatory mutations located immediately upstream and downstream of the original G33A mutation. The examination of the helix-loop-helix motif observed in the core protein structure (residues 15 to 41; Protein Data Bank entry 1CWX) indicated that the residues G33 and F24 are in close contact with each other, and that the G33A mutation induces a steric clash with F24. Molecular simulations revealed that the compensatory mutations increase the helix-loop-helix flexibility, allowing rescue of the core active conformation required for efficient virus production. Taken together, these data highlight the plasticity of core domain 1 conformation and illustrate the relationship between its structural tolerance to mutations and virus infectivity.

Item Type: Article
Journal or Publication Title: Journal of Virology
Uncontrolled Keywords: Amino Acid Sequence ; Cell Line ; Conserved Sequence ; Glycine ; Hepacivirus ; Hepatitis C ; Humans ; Molecular Sequence Data ; Protein Structure, Tertiary ; Sequence Alignment ; Viral Core Proteins ; Virus Replication
Subjects:
Departments: Faculty of Health and Medicine > Biomedical & Life Sciences
ID Code: 66855
Deposited By: ep_importer_pure
Deposited On: 27 Sep 2013 10:32
Refereed?: Yes
Published?: Published
Last Modified: 24 Nov 2017 05:27
Identification Number:
URI: http://eprints.lancs.ac.uk/id/eprint/66855

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