The N-terminal Helical Region of the Hepatitis C Virus p7 Ion Channel Protein Is Critical for Infectious Virus Production


Hepatitis C virus (HCV) infection can lead to significant liver disease and, without a vaccine, continues to pose a significant public health threat. The viral p7 protein is a multifunctional protein that is required for infectious virus production via its role in orchestrating virion assembly and its activity as an ion channel. However, while there is accumulating structural information on p7, there is no consensus on which conformation(s) exist during a natural infection or how structural elements relate to p7 functions. By comparing two prominent, yet highly divergent models of p7, we identified one region of structural similarity–the N-terminal helical region. While mutagenesis screening of other regions of the protein are in keeping with p7 conformational flexibility, mutations within the N-terminal helical region had a significant impact on infectious virus production, due in part to a loss of efficient E2/p7 cleavage. We further postulated the precise functional impact of mutations throughout p7 by homology modeling and demonstrated tolerance for diverse amino acid substitutions for specific N-terminal helix residues with putative ion channel defects. Together, these data not only support p7 as a structurally plastic, minimalistic ion channel, but also provide extensive insight into the p7 structure-function relationship and highlight the importance of the N-terminal helical region in E2/p7 processing, protein-protein interactions, ion channel activity, and infectious HCV production.


Vyšlo v časopise: The N-terminal Helical Region of the Hepatitis C Virus p7 Ion Channel Protein Is Critical for Infectious Virus Production. PLoS Pathog 11(11): e32767. doi:10.1371/journal.ppat.1005297
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005297

Souhrn

Hepatitis C virus (HCV) infection can lead to significant liver disease and, without a vaccine, continues to pose a significant public health threat. The viral p7 protein is a multifunctional protein that is required for infectious virus production via its role in orchestrating virion assembly and its activity as an ion channel. However, while there is accumulating structural information on p7, there is no consensus on which conformation(s) exist during a natural infection or how structural elements relate to p7 functions. By comparing two prominent, yet highly divergent models of p7, we identified one region of structural similarity–the N-terminal helical region. While mutagenesis screening of other regions of the protein are in keeping with p7 conformational flexibility, mutations within the N-terminal helical region had a significant impact on infectious virus production, due in part to a loss of efficient E2/p7 cleavage. We further postulated the precise functional impact of mutations throughout p7 by homology modeling and demonstrated tolerance for diverse amino acid substitutions for specific N-terminal helix residues with putative ion channel defects. Together, these data not only support p7 as a structurally plastic, minimalistic ion channel, but also provide extensive insight into the p7 structure-function relationship and highlight the importance of the N-terminal helical region in E2/p7 processing, protein-protein interactions, ion channel activity, and infectious HCV production.


Zdroje

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