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 replicase^{2, 3}, as well as a pivotal regulator of replication^{2, 4} and a modulator of cellular processes ranging from innate immunity to dysregulated cell growth^{5, 6}. NS5A is a large phosphoprotein (56−58 kDa) with an amphipathic -helix at its amino terminus that promotes membrane association^{7, 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 anchor^{7, 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.

1. Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, 1230 York Avenue Box 64, New York, New York 10021, USA

Correspondence to: Joseph Marcotrigiano¹Charles M. Rice¹ Correspondence and requests for materials should be addressed to C.M.R. (Email: ricec@rockefeller.edu) or J.M. ( Email: marcotj@rockefeller.edu).

Received 24 January 2005; Accepted 1 April 2005

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