TY - JOUR

T1 - Conserved glycine 33 residue in flexible domain I of hepatitis C virus core protein is critical for virus infectivity

AU - Angus, Allan G. N.

AU - Loquet, Antoine

AU - Stack, Séamus J.

AU - Dalrymple, David

AU - Gatherer, Derek

AU - Penin, François

AU - Patel, Arvind H.

PY - 2012/1

Y1 - 2012/1

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Cell Line

KW - Conserved Sequence

KW - Glycine

KW - Hepacivirus

KW - Hepatitis C

KW - Humans

KW - Molecular Sequence Data

KW - Protein Structure, Tertiary

KW - Sequence Alignment

KW - Viral Core Proteins

KW - Virus Replication

U2 - 10.1128/JVI.05452-11

DO - 10.1128/JVI.05452-11

M3 - Journal article

C2 - 22072760

VL - 86

SP - 679

EP - 690

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 2

ER -