5fw5

Structural highlights

Function

[G3BP1_HUMAN] May be a regulated effector of stress granule assembly. Phosphorylation-dependent sequence-specific endoribonuclease in vitro. Cleaves exclusively between cytosine and adenine and cleaves MYC mRNA preferentially at the 3'-UTR. ATP- and magnesium-dependent helicase. Unwinds preferentially partial DNA and RNA duplexes having a 17 bp annealed portion and either a hanging 3' tail or hanging tails at both 5'- and 3'-ends. Unwinds DNA/DNA, RNA/DNA, and RNA/RNA substrates with comparable efficiency. Acts unidirectionally by moving in the 5' to 3' direction along the bound single-stranded DNA.^{[1] [2]} [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.^{[3] [4] [5] [6] [7] [8] [9] [10]} 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.^{[11] [12] [13] [14] [15] [16] [17] [18]} 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.^{[19] [20] [21] [22] [23] [24] [25] [26]} nsP3 is essential for minus strand and subgenomic 26S mRNA synthesis.^{[27] [28] [29] [30] [31] [32] [33] [34]} 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.^{[35] [36] [37] [38] [39] [40] [41] [42]}

References

1. ↑ Costa M, Ochem A, Staub A, Falaschi A. Human DNA helicase VIII: a DNA and RNA helicase corresponding to the G3BP protein, an element of the ras transduction pathway. Nucleic Acids Res. 1999 Feb 1;27(3):817-21. PMID:9889278
2. ↑ Tourriere H, Gallouzi IE, Chebli K, Capony JP, Mouaikel J, van der Geer P, Tazi J. RasGAP-associated endoribonuclease G3Bp: selective RNA degradation and phosphorylation-dependent localization. Mol Cell Biol. 2001 Nov;21(22):7747-60. PMID:11604510 doi:10.1128/MCB.21.22.7747-7760.2001
3. ↑ 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
4. ↑ 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
5. ↑ 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
6. ↑ 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
7. ↑ 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
8. ↑ 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
9. ↑ 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
10. ↑ 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
11. ↑ 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
12. ↑ 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
13. ↑ 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
14. ↑ 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
15. ↑ 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
16. ↑ 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
17. ↑ 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
18. ↑ 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
19. ↑ 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
20. ↑ 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
21. ↑ 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
22. ↑ 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
23. ↑ 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
24. ↑ 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
25. ↑ 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
26. ↑ 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
27. ↑ 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
28. ↑ 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
29. ↑ 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
30. ↑ 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
31. ↑ 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
32. ↑ 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
33. ↑ 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
34. ↑ 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
35. ↑ 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
36. ↑ 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
37. ↑ 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
38. ↑ 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
39. ↑ 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
40. ↑ 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
41. ↑ 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
42. ↑ 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
43. ↑ Schulte T, Liu L, Panas MD, Thaa B, Dickson N, Gotte B, Achour A, McInerney GM. Combined structural, biochemical and cellular evidence demonstrates that both FGDF motifs in alphavirus nsP3 are required for efficient replication. Open Biol. 2016 Jul;6(7). pii: 160078. doi: 10.1098/rsob.160078. PMID:27383630 doi:http://dx.doi.org/10.1098/rsob.160078