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Sci Rep. 2019 Jun 10;9(1):8383. doi: 10.1038/s41598-019-44413-x.

Hepatitis C virus sequence divergence preserves p7 viroporin structural and dynamic features.

Author information

1
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom.
2
Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom.
3
Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RY, United Kingdom.
4
Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.
5
Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Pleinlaan 2, 1050, Brussels, Belgium.
6
Laboratoire International Associé CNRS-University of Illinois at Urbana Champaign, Université de Lorraine, BP 70239, 54506, Vandœuvre-lès-Nancy, France.
7
Department of Physics, University of Illinois at Urbana-Champaign, 1110 West Green Street, Urbana, Illinois, 61801, United States.
8
Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom. Jason.Schnell@bioch.ox.ac.uk.
9
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom. Nicole.Zitzmann@bioch.ox.ac.uk.

Abstract

The hepatitis C virus (HCV) viroporin p7 oligomerizes to form ion channels, which are required for the assembly and secretion of infectious viruses. The 63-amino acid p7 monomer has two putative transmembrane domains connected by a cytosolic loop, and has both N- and C- termini exposed to the endoplasmic reticulum (ER) lumen. NMR studies have indicated differences between p7 structures of distantly related HCV genotypes. A critical question is whether these differences arise from the high sequence variation between the different isolates and if so, how the divergent structures can support similar biological functions. Here, we present a side-by-side characterization of p7 derived from genotype 1b (isolate J4) in the detergent 6-cyclohexyl-1-hexylphosphocholine (Cyclofos-6) and p7 derived from genotype 5a (isolate EUH1480) in n-dodecylphosphocholine (DPC). The 5a isolate p7 in conditions previously associated with a disputed oligomeric form exhibits secondary structure, dynamics, and solvent accessibility broadly like those of the monomeric 1b isolate p7. The largest differences occur at the start of the second transmembrane domain, which is destabilized in the 5a isolate. The results show a broad consensus among the p7 variants that have been studied under a range of different conditions and indicate that distantly related HCVs preserve key features of structure and dynamics.

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