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Virus Res. 2013 Dec 26;178(2):553-6. doi: 10.1016/j.virusres.2013.07.020. Epub 2013 Aug 23.

Molecular characterization of hepatitis E virus ORF1 gene supports a papain-like cysteine protease (PCP)-domain activity.

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Department of Pharmacognosy, King Saud University College of Pharmacy, PO Box 2457, Riyadh 11451, Saudi Arabia. Electronic address:


Hepatitis E Virus (HEV) ORF1 encodes the nonstructural polyprotein wherein a role of PCP-domain in ORF1 proteolysis and/or RNA replication still remains contested. A series of ORF1 mutants of HEV-SAR55 replicon were constructed and tested for viability in S10-3 cells. Six of PCP-'cysteine' (C457A, C459A, C471A, C472A, C481A and C483A) and three 'histidine' (H443L, H497L and H590L) mutants were lethal. Further, a highly conserved 'glycine-triad' (G815-G816-G817) in downstream X-domain, homologous to rubella virus protease-substrate (G1299-G1300-G1301) was identified where two of X-mutants (G816V and G817V) turned lethal. However, all ORF1 sequential nucleotide-mutants conserving the amino acids were viable, which clearly showed post-translational regulation of HEV replication by PCP- and X-domains. Moreover, while vector-expressed ORF1-fusion polyprotein yielded a ~191 kDa band in vitro, it produced ~78 and ~35 kDa fragments ex vivo. Collectively, the indispensability and functional effects of 'PCP-catalytic' and 'X-substrate' residues on HEV replication strongly supported a viral protease.


Genomic replicon; HEV; Hepatitis E virus; ORF-1; Papain-like cysteine protease

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