Abstract
Homologues of the selenoprotein glutathione peroxidase (GPx) have been previously identified in poxviruses and in RNA viruses including HIV-1 and hepatitis C virus (HCV). Sequence analysis of the NS4 region of Japanese encephalitis virus (JEV) suggests it may encode a structurally related but functionally distinct selenoprotein gene, more closely related to the iron-binding protein ferredoxin than to GPx, with three highly conserved UGA codons that align with essential Cys residues of ferredoxin. Comparison of the probe JEV sequence to an aligned family of ferredoxin sequences gave an overall 30.3% identity and 45.8% similarity, and was statistically significant at 4.9 S.D. ( P < 10 −6) above the average score computed for randomly shuffled sequences. A 3-dimensional model of the hypothetical JEV protein (JEV model) was constructed by homology modeling using SYBYL, based upon a high resolution X-ray structure of ferredoxin (PDB code: 1awd). The JEV model and the model from 1awd were subsequently subjected to molecular dynamics simulations in aqueous medium using AMBER 6. The solution structure of the JEV model indicates that it could fold into a tertiary structure globally similar to ferredoxin 1awd, with RMSD between the averaged structures of 1.8 Å for the aligned regions. The modeling and MD simulations data also indicate that this structure for the JEV protein is energetically favorable, and that it could be quite stable at room temperature. This protein might play a role in JEV infection and replication via TNF and other cellular stimuli mediated via redox mechanisms.
Highlights
The flavivirus family (Flaviviridae) consists of three genera: the pestviruses; the hepaciviruses, to which belongs hepatitis C virus (HCV); and the flaviviruses
In order to investigate the structure and function of the hypothetical protein encoded in the −1 reading frame of the NS4 region of Japanese encephalitis virus (JEV), 15 full genomic JEV sequences were selected from GenBank
60 nucleotides upstream of the first in-frame UGA codon we identified a conserved ATG start codon in the context of a Kozak-like sequence GCTCCCTGGATGG, which is substantially similar to the ideal Kozak sequence GCCGCCRCCATGG
Summary
The flavivirus family (Flaviviridae) consists of three genera: the pestviruses; the hepaciviruses, to which belongs hepatitis C virus (HCV); and the flaviviruses. In addition to HCV, major human pathogens among the flaviviruses include Japanese encephalitis virus (JEV), dengue fever virus (DENV), yellow fever virus (YFV), and West Nile virus (WNV). JEV virus is a small enveloped virus containing a positive-strand RNA genome of approximately 11 kb. The genome is translated as a long open reading frame encoding a polyprotein which can be cleaved post- and co-translationally to generate 10 proteins in the gene order 5′-C-prM-E-NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5-3′. Among these 10 proteins, the capsid protein C, the premembrane protein prM and the envelope protein E are structural proteins, while NS1 to NS5 proteins represent nonstructural proteins. The structure and function of NS4B coding region, has received relatively little attention and its function is poorly understood [1]
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