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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
Gene Review

nsP4  - 

Salmon pancreas disease virus

 
 
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Disease relevance of nsP4

 

High impact information on nsP4

  • This sequence of delayed processing of P1234 would explain the accumulation of P123 plus nsP4, the early short-lived minus-strand replicase [5].
  • These results suggest that while selection of ONNV variants is occurring, de novo mutation at the position between nsP3 and nsP4 does not readily occur in the mosquito [6].
  • Effects of an Opal Termination Codon Preceding the nsP4 Gene Sequence in the O'Nyong-Nyong Virus Genome on Anopheles gambiae Infectivity [6].
  • The presence of an opal stop codon upstream of nsP4 nearly doubled (75.5%) the infectivity of ONNV over that of virus possessing a codon for the amino acid arginine at the corresponding position (39.8%) [6].
  • Catalytic Core of Alphavirus Nonstructural Protein nsP4 Possesses Terminal Adenylyltransferase Activity [1].
 

Chemical compound and disease context of nsP4

  • Recent insights into the early events in Sindbis virus RNA replication suggest a requirement for either the P123 or P23 polyprotein, as well as mature nsP4, the RNA-dependent RNA polymerase, for initiation of minus-strand RNA synthesis [7].
  • We found that Ross River virus possesses an in-phase opal termination codon between nsP3 and nsP4, whereas in O'Nyong-nyong virus this termination codon is replaced by an arginine codon [8].
  • Previously we reported that the N-terminal Tyr residue of nsP4 of Sindbis virus, the type species of the genus Alphavirus, can be substituted with Phe, Trp, or His without altering the wild-type phenotype in cultured cells but that other substitutions tested, except for Met, were lethal or quasilethal [9].
 

Biological context of nsP4

  • In chicken cells, the nsP4 Arg183 mutants had a nonconditionally lethal, temperature-sensitive (ts) growth phenotype caused by a ts defect in minus-strand synthesis whose extent varied with the particular amino acid substituted (Ser>Ala>Lys) [10].
  • Previous studies (D.L. Sawicki, D. B. Barkhimer, S. G. Sawicki, C. M. Rice, and S. Schlesinger, Virology 174:43-52, 1990) identified a temperature-sensitive (ts) defect in Sindbis virus nonstructural protein 4 (nsP4) that reactivated negative-strand synthesis after its normal cessation at the end of the early phase of replication [11].
  • The core catalytic domain of nsP4 (Delta97nsP4, a deletion of the N-terminal 97 amino acids), which consists of the predicted polymerase domain containing the GDD amino acid motif required for viral RNA synthesis, was stable against proteolytic degradation during expression [1].
  • All three suppressor mutations suppressed the effects of Ala, Arg, or Leu at the N-terminus of nsP4 with almost equal efficiency and thus the effect of the suppressing mutation is independent of the nsP4 N-terminal residue [9].
 

Anatomical context of nsP4

 

Associations of nsP4 with chemical compounds

  • These mutations resulted in the following amino acid changes in nsP4: leucine to valine at residue 48, aspartate to glycine at residue 142, and proline to arginine at residue 187 [13].
  • (4) SFV mutants that produce nsP1, P23, nsP4, as well as the precursor P123 are viable but produce an order of magnitude less virus than wild type at 30 degrees C and two orders of magnitude less virus at 39 degrees C. The ratio of subgenomic mRNA to genomic RNA is much reduced in these mutants relative to the parental viruses [14].
  • A unique base change of an A for a C residue at nt 6339, predicting a change from glutamine to lysine at amino acid 195 in nsP4, was found in genomes of ts24, ts24R1, and ts24R2 [15].
 

Physical interactions of nsP4

  • However, the nsP3 of both ts4 and ts7 allowed reactivation of negative-strand synthesis by stable replication complexes containing nsP4 from ts24 [16].
  • The results from this study and from a previous report on the shutoff of minus-strand RNA synthesis at 40 degrees C with the nsP1-A348T mutation in ts11 suggests that the N-terminus nsP4 interacts with nsP1 during initiation of minus-strand RNA synthesis [9].
 

Other interactions of nsP4

  • The membrane-associated alphavirus RNA replication complex contains four virus-encoded subunits, the nonstructural proteins nsP1 to nsP4 [17].
  • Reactivation of negative-strand synthesis by mutations in nsP2 resembled that in nsP4: it was a reversible property of stable replication complexes and did not require continuation of viral protein synthesis [11].
  • We designed 4 primer pairs to amplify conserved regions of the E1 or nsP4 genes of salmonid alphavirus (SAV) and evaluated their performance in optimized 1-step SYBR green real-time RT-PCR (RRT-PCR) assays [18].
 

Analytical, diagnostic and therapeutic context of nsP4

  • Functional mapping and sequence analysis of the mutant cDNAs revealed several mutations which mapped to the amino terminus of nsP4, the putative polymerase subunit of the viral RNA replicase [13].

References

  1. Catalytic Core of Alphavirus Nonstructural Protein nsP4 Possesses Terminal Adenylyltransferase Activity. Tomar, S., Hardy, R.W., Smith, J.L., Kuhn, R.J. J. Virol. (2006) [Pubmed]
  2. Modification of the 5' terminus of Sindbis virus genomic RNA allows nsP4 RNA polymerases with nonaromatic amino acids at the N terminus to function in RNA replication. Shirako, Y., Strauss, E.G., Strauss, J.H. J. Virol. (2003) [Pubmed]
  3. Recombinational history and molecular evolution of western equine encephalomyelitis complex alphaviruses. Weaver, S.C., Kang, W., Shirako, Y., Rumenapf, T., Strauss, E.G., Strauss, J.H. J. Virol. (1997) [Pubmed]
  4. Nucleotide sequence of the genome region encoding the 26S mRNA of eastern equine encephalomyelitis virus and the deduced amino acid sequence of the viral structural proteins. Chang, G.J., Trent, D.W. J. Gen. Virol. (1987) [Pubmed]
  5. Regulation of the sequential processing of Semliki Forest virus replicase polyprotein. Vasiljeva, L., Merits, A., Golubtsov, A., Sizemskaja, V., Kääriäinen, L., Ahola, T. J. Biol. Chem. (2003) [Pubmed]
  6. Effects of an Opal Termination Codon Preceding the nsP4 Gene Sequence in the O'Nyong-Nyong Virus Genome on Anopheles gambiae Infectivity. Myles, K.M., Kelly, C.L., Ledermann, J.P., Powers, A.M. J. Virol. (2006) [Pubmed]
  7. Template-dependent initiation of Sindbis virus RNA replication in vitro. Lemm, J.A., Bergqvist, A., Read, C.M., Rice, C.M. J. Virol. (1998) [Pubmed]
  8. Nonstructural proteins nsP3 and nsP4 of Ross River and O'Nyong-nyong viruses: sequence and comparison with those of other alphaviruses. Strauss, E.G., Levinson, R., Rice, C.M., Dalrymple, J., Strauss, J.H. Virology (1988) [Pubmed]
  9. Suppressor mutations that allow sindbis virus RNA polymerase to function with nonaromatic amino acids at the N-terminus: evidence for interaction between nsP1 and nsP4 in minus-strand RNA synthesis. Shirako, Y., Strauss, E.G., Strauss, J.H. Virology (2000) [Pubmed]
  10. Alphavirus minus-strand RNA synthesis: identification of a role for Arg183 of the nsP4 polymerase. Fata, C.L., Sawicki, S.G., Sawicki, D.L. J. Virol. (2002) [Pubmed]
  11. A second nonstructural protein functions in the regulation of alphavirus negative-strand RNA synthesis. Sawicki, D.L., Sawicki, S.G. J. Virol. (1993) [Pubmed]
  12. The alphavirus replicase protein nsP1 is membrane-associated and has affinity to endocytic organelles. Peränen, J., Laakkonen, P., Hyvönen, M., Kääriäinen, L. Virology (1995) [Pubmed]
  13. Mutations which alter the level or structure of nsP4 can affect the efficiency of Sindbis virus replication in a host-dependent manner. Lemm, J.A., Durbin, R.K., Stollar, V., Rice, C.M. J. Virol. (1990) [Pubmed]
  14. Regulation of Semliki Forest virus RNA replication: a model for the control of alphavirus pathogenesis in invertebrate hosts. Kim, K.H., Rümenapf, T., Strauss, E.G., Strauss, J.H. Virology (2004) [Pubmed]
  15. Temperature sensitive shut-off of alphavirus minus strand RNA synthesis maps to a nonstructural protein, nsP4. Sawicki, D., Barkhimer, D.B., Sawicki, S.G., Rice, C.M., Schlesinger, S. Virology (1990) [Pubmed]
  16. Alphavirus nsP3 functions to form replication complexes transcribing negative-strand RNA. Wang, Y.F., Sawicki, S.G., Sawicki, D.L. J. Virol. (1994) [Pubmed]
  17. Effects of palmitoylation of replicase protein nsP1 on alphavirus infection. Ahola, T., Kujala, P., Tuittila, M., Blom, T., Laakkonen, P., Hinkkanen, A., Auvinen, P. J. Virol. (2000) [Pubmed]
  18. Development and evaluation of a one-step real-time reverse transcription polymerase chain reaction assay for the detection of salmonid alphaviruses in serum and tissues. Graham, D.A., Taylor, C., Rodgers, D., Weston, J., Khalili, M., Ball, N., Christie, K.E., Todd, D. Dis. Aquat. Org. (2006) [Pubmed]
 
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