1fw5

Structural highlights

Function

POLN_SFV P123 is short-lived polyproteins, accumulating during early stage of infection. It localizes the viral replication complex to the cytoplasmic surface of modified endosomes and lysosomes. By interacting with nsP4, it starts viral genome replication into antigenome. After these early events, P123 is cleaved sequentially into nsP1, nsP2 and nsP3. This sequence of delayed processing would allow correct assembly and membrane association of the RNA polymerase complex.^{[1] [2] [3] [4] [5] [6] [7] [8]} nsP1 is a cytoplasmic capping enzyme. This function is necessary since all viral RNAs are synthesized in the cytoplasm, and host capping enzymes are restricted to the nucleus. The enzymatic reaction involves a covalent link between 7-methyl-GMP and nsP1, whereas eukaryotic capping enzymes form a covalent complex only with GMP. nsP1 capping would consist in the following reactions: GTP is first methylated and then forms the m7GMp-nsP1 complex, from which 7-methyl-GMP complex is transferred to the mRNA to create the cap structure. Palmitoylated nsP1 is remodeling host cell cytoskeleton, and induces filopodium-like structure formation at the surface of the host cell.^{[9] [10] [11] [12] [13] [14] [15] [16]} nsP2 has two separate domain with different biological activities. The N-terminal section is part of the RNA polymerase complex and has RNA trisphosphatase and RNA helicase activity. The C-terminal section harbors a protease that specifically cleaves and releases the four mature proteins. Also inhibits cellular transcription by inducing rapid degradation of POLR2A, a catalytic subunit of the RNAPII complex. The resulting inhibition of cellular protein synthesis serves to ensure maximal viral gene expression and to evade host immune response.^{[17] [18] [19] [20] [21] [22] [23] [24]} nsP3 is essential for minus strand and subgenomic 26S mRNA synthesis.^{[25] [26] [27] [28] [29] [30] [31] [32]} nsP4 is an RNA dependent RNA polymerase. It replicates genomic and antigenomic RNA by recognizing replications specific signals. Transcribes also a 26S subgenomic mRNA by initiating RNA synthesis internally on antigenomic RNA. This 26S mRNA codes for structural proteins.^{[33] [34] [35] [36] [37] [38] [39] [40]}

See Also

• Nonstructural protein 3D structures

References

1. ↑ Rikkonen M, Peranen J, Kaariainen L. ATPase and GTPase activities associated with Semliki Forest virus nonstructural protein nsP2. J Virol. 1994 Sep;68(9):5804-10. PMID:8057461
2. ↑ Ahola T, Kaariainen L. Reaction in alphavirus mRNA capping: formation of a covalent complex of nonstructural protein nsP1 with 7-methyl-GMP. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):507-11. PMID:7831320
3. ↑ Ahola T, Laakkonen P, Vihinen H, Kaariainen L. Critical residues of Semliki Forest virus RNA capping enzyme involved in methyltransferase and guanylyltransferase-like activities. J Virol. 1997 Jan;71(1):392-7. PMID:8985362
4. ↑ Laakkonen P, Auvinen P, Kujala P, Kaariainen L. Alphavirus replicase protein NSP1 induces filopodia and rearrangement of actin filaments. J Virol. 1998 Dec;72(12):10265-9. PMID:9811773
5. ↑ Gomez de Cedron M, Ehsani N, Mikkola ML, Garcia JA, Kaariainen L. RNA helicase activity of Semliki Forest virus replicase protein NSP2. FEBS Lett. 1999 Apr 1;448(1):19-22. PMID:10217401
6. ↑ Vasiljeva L, Merits A, Auvinen P, Kaariainen L. Identification of a novel function of the alphavirus capping apparatus. RNA 5'-triphosphatase activity of Nsp2. J Biol Chem. 2000 Jun 9;275(23):17281-7. PMID:10748213 doi:http://dx.doi.org/10.1074/jbc.M910340199
7. ↑ Sawicki DL, Perri S, Polo JM, Sawicki SG. Role for nsP2 proteins in the cessation of alphavirus minus-strand synthesis by host cells. J Virol. 2006 Jan;80(1):360-71. PMID:16352561 doi:http://dx.doi.org/10.1128/JVI.80.1.360-371.2006
8. ↑ Akhrymuk I, Kulemzin SV, Frolova EI. Evasion of the innate immune response: the Old World alphavirus nsP2 protein induces rapid degradation of Rpb1, a catalytic subunit of RNA polymerase II. J Virol. 2012 Jul;86(13):7180-91. doi: 10.1128/JVI.00541-12. Epub 2012 Apr 18. PMID:22514352 doi:http://dx.doi.org/10.1128/JVI.00541-12
9. ↑ Rikkonen M, Peranen J, Kaariainen L. ATPase and GTPase activities associated with Semliki Forest virus nonstructural protein nsP2. J Virol. 1994 Sep;68(9):5804-10. PMID:8057461
10. ↑ Ahola T, Kaariainen L. Reaction in alphavirus mRNA capping: formation of a covalent complex of nonstructural protein nsP1 with 7-methyl-GMP. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):507-11. PMID:7831320
11. ↑ Ahola T, Laakkonen P, Vihinen H, Kaariainen L. Critical residues of Semliki Forest virus RNA capping enzyme involved in methyltransferase and guanylyltransferase-like activities. J Virol. 1997 Jan;71(1):392-7. PMID:8985362
12. ↑ Laakkonen P, Auvinen P, Kujala P, Kaariainen L. Alphavirus replicase protein NSP1 induces filopodia and rearrangement of actin filaments. J Virol. 1998 Dec;72(12):10265-9. PMID:9811773
13. ↑ Gomez de Cedron M, Ehsani N, Mikkola ML, Garcia JA, Kaariainen L. RNA helicase activity of Semliki Forest virus replicase protein NSP2. FEBS Lett. 1999 Apr 1;448(1):19-22. PMID:10217401
14. ↑ Vasiljeva L, Merits A, Auvinen P, Kaariainen L. Identification of a novel function of the alphavirus capping apparatus. RNA 5'-triphosphatase activity of Nsp2. J Biol Chem. 2000 Jun 9;275(23):17281-7. PMID:10748213 doi:http://dx.doi.org/10.1074/jbc.M910340199
15. ↑ Sawicki DL, Perri S, Polo JM, Sawicki SG. Role for nsP2 proteins in the cessation of alphavirus minus-strand synthesis by host cells. J Virol. 2006 Jan;80(1):360-71. PMID:16352561 doi:http://dx.doi.org/10.1128/JVI.80.1.360-371.2006
16. ↑ Akhrymuk I, Kulemzin SV, Frolova EI. Evasion of the innate immune response: the Old World alphavirus nsP2 protein induces rapid degradation of Rpb1, a catalytic subunit of RNA polymerase II. J Virol. 2012 Jul;86(13):7180-91. doi: 10.1128/JVI.00541-12. Epub 2012 Apr 18. PMID:22514352 doi:http://dx.doi.org/10.1128/JVI.00541-12
17. ↑ Rikkonen M, Peranen J, Kaariainen L. ATPase and GTPase activities associated with Semliki Forest virus nonstructural protein nsP2. J Virol. 1994 Sep;68(9):5804-10. PMID:8057461
18. ↑ Ahola T, Kaariainen L. Reaction in alphavirus mRNA capping: formation of a covalent complex of nonstructural protein nsP1 with 7-methyl-GMP. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):507-11. PMID:7831320
19. ↑ Ahola T, Laakkonen P, Vihinen H, Kaariainen L. Critical residues of Semliki Forest virus RNA capping enzyme involved in methyltransferase and guanylyltransferase-like activities. J Virol. 1997 Jan;71(1):392-7. PMID:8985362
20. ↑ Laakkonen P, Auvinen P, Kujala P, Kaariainen L. Alphavirus replicase protein NSP1 induces filopodia and rearrangement of actin filaments. J Virol. 1998 Dec;72(12):10265-9. PMID:9811773
21. ↑ Gomez de Cedron M, Ehsani N, Mikkola ML, Garcia JA, Kaariainen L. RNA helicase activity of Semliki Forest virus replicase protein NSP2. FEBS Lett. 1999 Apr 1;448(1):19-22. PMID:10217401
22. ↑ Vasiljeva L, Merits A, Auvinen P, Kaariainen L. Identification of a novel function of the alphavirus capping apparatus. RNA 5'-triphosphatase activity of Nsp2. J Biol Chem. 2000 Jun 9;275(23):17281-7. PMID:10748213 doi:http://dx.doi.org/10.1074/jbc.M910340199
23. ↑ Sawicki DL, Perri S, Polo JM, Sawicki SG. Role for nsP2 proteins in the cessation of alphavirus minus-strand synthesis by host cells. J Virol. 2006 Jan;80(1):360-71. PMID:16352561 doi:http://dx.doi.org/10.1128/JVI.80.1.360-371.2006
24. ↑ Akhrymuk I, Kulemzin SV, Frolova EI. Evasion of the innate immune response: the Old World alphavirus nsP2 protein induces rapid degradation of Rpb1, a catalytic subunit of RNA polymerase II. J Virol. 2012 Jul;86(13):7180-91. doi: 10.1128/JVI.00541-12. Epub 2012 Apr 18. PMID:22514352 doi:http://dx.doi.org/10.1128/JVI.00541-12
25. ↑ Rikkonen M, Peranen J, Kaariainen L. ATPase and GTPase activities associated with Semliki Forest virus nonstructural protein nsP2. J Virol. 1994 Sep;68(9):5804-10. PMID:8057461
26. ↑ Ahola T, Kaariainen L. Reaction in alphavirus mRNA capping: formation of a covalent complex of nonstructural protein nsP1 with 7-methyl-GMP. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):507-11. PMID:7831320
27. ↑ Ahola T, Laakkonen P, Vihinen H, Kaariainen L. Critical residues of Semliki Forest virus RNA capping enzyme involved in methyltransferase and guanylyltransferase-like activities. J Virol. 1997 Jan;71(1):392-7. PMID:8985362
28. ↑ Laakkonen P, Auvinen P, Kujala P, Kaariainen L. Alphavirus replicase protein NSP1 induces filopodia and rearrangement of actin filaments. J Virol. 1998 Dec;72(12):10265-9. PMID:9811773
29. ↑ Gomez de Cedron M, Ehsani N, Mikkola ML, Garcia JA, Kaariainen L. RNA helicase activity of Semliki Forest virus replicase protein NSP2. FEBS Lett. 1999 Apr 1;448(1):19-22. PMID:10217401
30. ↑ Vasiljeva L, Merits A, Auvinen P, Kaariainen L. Identification of a novel function of the alphavirus capping apparatus. RNA 5'-triphosphatase activity of Nsp2. J Biol Chem. 2000 Jun 9;275(23):17281-7. PMID:10748213 doi:http://dx.doi.org/10.1074/jbc.M910340199
31. ↑ Sawicki DL, Perri S, Polo JM, Sawicki SG. Role for nsP2 proteins in the cessation of alphavirus minus-strand synthesis by host cells. J Virol. 2006 Jan;80(1):360-71. PMID:16352561 doi:http://dx.doi.org/10.1128/JVI.80.1.360-371.2006
32. ↑ Akhrymuk I, Kulemzin SV, Frolova EI. Evasion of the innate immune response: the Old World alphavirus nsP2 protein induces rapid degradation of Rpb1, a catalytic subunit of RNA polymerase II. J Virol. 2012 Jul;86(13):7180-91. doi: 10.1128/JVI.00541-12. Epub 2012 Apr 18. PMID:22514352 doi:http://dx.doi.org/10.1128/JVI.00541-12
33. ↑ Rikkonen M, Peranen J, Kaariainen L. ATPase and GTPase activities associated with Semliki Forest virus nonstructural protein nsP2. J Virol. 1994 Sep;68(9):5804-10. PMID:8057461
34. ↑ Ahola T, Kaariainen L. Reaction in alphavirus mRNA capping: formation of a covalent complex of nonstructural protein nsP1 with 7-methyl-GMP. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):507-11. PMID:7831320
35. ↑ Ahola T, Laakkonen P, Vihinen H, Kaariainen L. Critical residues of Semliki Forest virus RNA capping enzyme involved in methyltransferase and guanylyltransferase-like activities. J Virol. 1997 Jan;71(1):392-7. PMID:8985362
36. ↑ Laakkonen P, Auvinen P, Kujala P, Kaariainen L. Alphavirus replicase protein NSP1 induces filopodia and rearrangement of actin filaments. J Virol. 1998 Dec;72(12):10265-9. PMID:9811773
37. ↑ Gomez de Cedron M, Ehsani N, Mikkola ML, Garcia JA, Kaariainen L. RNA helicase activity of Semliki Forest virus replicase protein NSP2. FEBS Lett. 1999 Apr 1;448(1):19-22. PMID:10217401
38. ↑ Vasiljeva L, Merits A, Auvinen P, Kaariainen L. Identification of a novel function of the alphavirus capping apparatus. RNA 5'-triphosphatase activity of Nsp2. J Biol Chem. 2000 Jun 9;275(23):17281-7. PMID:10748213 doi:http://dx.doi.org/10.1074/jbc.M910340199
39. ↑ Sawicki DL, Perri S, Polo JM, Sawicki SG. Role for nsP2 proteins in the cessation of alphavirus minus-strand synthesis by host cells. J Virol. 2006 Jan;80(1):360-71. PMID:16352561 doi:http://dx.doi.org/10.1128/JVI.80.1.360-371.2006
40. ↑ Akhrymuk I, Kulemzin SV, Frolova EI. Evasion of the innate immune response: the Old World alphavirus nsP2 protein induces rapid degradation of Rpb1, a catalytic subunit of RNA polymerase II. J Virol. 2012 Jul;86(13):7180-91. doi: 10.1128/JVI.00541-12. Epub 2012 Apr 18. PMID:22514352 doi:http://dx.doi.org/10.1128/JVI.00541-12
41. ↑ Lampio A, Kilpelainen I, Pesonen S, Karhi K, Auvinen P, Somerharju P, Kaariainen L. Membrane binding mechanism of an RNA virus-capping enzyme. J Biol Chem. 2000 Dec 1;275(48):37853-9. PMID:10984480 doi:10.1074/jbc.M004865200