title: The N-terminal Helical Region of the Hepatitis C Virus p7 Ion Channel Protein Is Critical for Infectious Virus Production.
abstract: The hepatitis C virus (HCV) p7 protein is required for infectious virus production via its role in assembly and ion channel activity. Although NMR structures of p7 have been reported, the location of secondary structural elements and orientation of the p7 transmembrane domains differ among models. Furthermore, the p7 structure-function relationship remains unclear. Here, extensive mutagenesis, coupled with infectious virus production phenotyping and molecular modeling, demonstrates that the N-terminal helical region plays a previously underappreciated yet critical functional role, especially with respect to E2/p7 cleavage efficiency. Interrogation of specific N-terminal helix residues identified as having p7-specific defects and predicted to point toward the channel pore, in a context of independent E2/p7 cleavage, further supports p7 as a structurally plastic, minimalist ion channel. Together, our findings indicate that the p7 N-terminal helical region is critical for E2/p7 processing, protein-protein interactions, ion channel activity, and infectious HCV production.
authors.affiliation: Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, United States of America.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Scull
authors.affiliation: Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, United States of America.
authors.forename: William M
authors.initials: WM
authors.lastname: Schneider
authors.affiliation: Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, United States of America.
authors.forename: Brenna R
authors.initials: BR
authors.lastname: Flatley
authors.affiliation: Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Hayden
authors.affiliation: Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, United States of America.
authors.forename: Canny
authors.initials: C
authors.lastname: Fung
authors.affiliation: Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, United States of America.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Jones
authors.affiliation: Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, United States of America.
authors.forename: Marieke
authors.initials: M
authors.lastname: van de Belt
authors.affiliation: Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, Labex Ecofect, Université Lyon 1, France; CNRS, UMR 5086, Lyon, France.
authors.forename: François
authors.initials: F
authors.lastname: Penin
authors.affiliation: Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, United States of America.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D008958:Models, Molecular; D014759:Viral Envelope Proteins / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*; D019065:Virus Assembly; D014779:Virus Replication; D000086082:Viroporin Proteins
chemical_list: D007473:Ion Channels; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C088369:p7 protein, Hepatitis C virus; D000086082:Viroporin Proteins