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).

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.

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