2lif

Publication Abstract from PubMed

Maturation of hepatitis C virus (HCV) core protein requires proteolytic processing by two host proteases: signal peptidase (SP) and the intra-membrane cleaving protease signal peptide peptidase (SPP). Previous work on HCV genotype (GT) 1a and 2a has identified crucial residues required for efficient signal peptide processing by SPP which in turn has an effect on production of infectious virus particles. Here we demonstrate that the JFH1 GT2a core-E1 signal peptide can be adapted to the GT3a sequence without affecting the production of infectious HCV. Through mutagenesis studies, we identified crucial residues required for core-E1 signal peptide processing, including a GT3a sequence specific histidine (His) at position 187. In addition, stable knockdown of intracellular SPP levels in HuH-7 cells significantly affects HCV virus titers, further demonstrating the requirement for SPP for maturation of core and production of infectious HCV particles. Finally, our NMR structural analysis of a synthetic HCV JFH1 GT2a core-E1 signal peptide provides an essential structural template for further understanding of core processing, as well as the first model for an SPP substrate within its membrane environment. Our findings give deeper insights into the mechanisms of intra-membrane cleaving proteases and the impact on viral infections.

Structural analysis of Hepatitis C Virus Core-E1 Signal Peptide and Requirements for Cleavage of the Genotype 3a Signal Sequence by Signal Peptide Peptidase.,Oehler V, Filipe A, Montserret R, da Costa D, Brown G, Penin F, McLauchlan J J Virol. 2012 May 16. PMID:22593157^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.