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Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase

Author

Listed:
  • Timothy L. Tellinghuisen

    (The Rockefeller University)

  • Joseph Marcotrigiano

    (The Rockefeller University)

  • Charles M. Rice

    (The Rockefeller University)

Abstract

Hepatitis C virus (HCV) is a human pathogen affecting nearly 3% of the world's population1. Chronic infections can lead to cirrhosis and liver cancer. The RNA replication machine of HCV is a multi-subunit membrane-associated complex. The non-structural protein NS5A is an active component of HCV replicase2,3, as well as a pivotal regulator of replication2,4 and a modulator of cellular processes ranging from innate immunity to dysregulated cell growth5,6. NS5A is a large phosphoprotein (56–58 kDa) with an amphipathic α-helix at its amino terminus that promotes membrane association7,8,9. After this helix region, NS5A is organized into three domains10. The N-terminal domain (domain I) coordinates a single zinc atom per protein molecule10. Mutations disrupting either the membrane anchor7,8 or zinc binding10 of NS5A are lethal for RNA replication. However, probing the role of NS5A in replication has been hampered by a lack of structural information about this multifunctional protein. Here we report the structure of NS5A domain I at 2.5-Å resolution, which contains a novel fold, a new zinc-coordination motif and a disulphide bond. We use molecular surface analysis to suggest the location of protein-, RNA- and membrane-interaction sites.

Suggested Citation

  • Timothy L. Tellinghuisen & Joseph Marcotrigiano & Charles M. Rice, 2005. "Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase," Nature, Nature, vol. 435(7040), pages 374-379, May.
    • Handle: RePEc:nat:nature:v:435:y:2005:i:7040:d:10.1038_nature03580
    DOI: 10.1038/nature03580
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    Cited by:

    1. Markus M. Knodel & Paul Targett-Adams & Alfio Grillo & Eva Herrmann & Gabriel Wittum, 2019. "Advanced Hepatitis C Virus Replication PDE Models within a Realistic Intracellular Geometric Environment," IJERPH, MDPI, vol. 16(3), pages 1-53, February.

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