SARS-CoV-2 protein NSP10
From Proteopedia
FunctionNsp10 or replicase polyprotein 1ab plays a pivotal role in SARS-CoV viral transcription by stimulating both Nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities and therefore plays an essential role in viral mRNAs cap methylation [1][2]. Nsp10 is translated as part of the polyprotein pp1ab, which is subsequently processed by the Main protease (SARS-CoV-2_Coronavirus_Main_Protease) and Papain-like protease (SARS-CoV-2_enzyme_Papain-like) into individual functional proteins. Nsp10 is a single domain protein made up of 139 residues and binds two zinc ions[1][2]. Nsp10 can bind single stranded and double stranded RNA and DNA and has been shown to have an allosteric effect on Nsp14 exoribonuclease activity which allows the exoribonuclease active site to form the substrate binding pocket increasing activity by 35 fold[3]<[4]. Similarly, the allosteric interaction of Nsp10 with Nsp16 allows for a more effective binding of mRNA for 2’O-methylation[5]. DiseaseSARS-CoV-2 is the cause of a global COVID-19 pandemic which started in 2019. RelevanceSARS-CoV-2 Non-structural protein 10 (Nsp10) has two independent allosteric interactions with Nsp14 and Nsp16. Structural highlightsNsp10 exhibits a novel fold currently found only in coronavirus related to SARS-CoV-2 [6][7]. The secondary structure of Nsp10 consists of 5 α-helices, a single 310-helix, and three β-strands. The two N-terminal α-helices (α1 and α2) are positioned away from the core of the protein. The core has an antiparallel β-sheet of all three β-strands adjacent to helices α3 and α4. Helices α3 and α4 coordinate the first zinc binding site through residues Cys74, Cys77, His83, and Cys90. The second zinc binding site is found at the C-terminus coordinated by Cys117, Cys120, Cys128, and Cys130, shortly after the single 310-helix and helix α5. Nsp10 has been found to form a heterodimer with either Nsp14 or Nsp16. The interaction between Nsp10 and Nsp14 is between the first four α-helices of Nsp10 and an antiparallel β-sheet (β1, β5, and β6) of Nsp14 (interface 7,798 Å2). The interaction between Nsp10 and Nsp16 is between α2, α3, and α4 of Nsp10 and β4, α3, α4 and α10 of Nsp16 (interface 1983 Å2). The two interface sites have some overlap. One structure of Nsp10 on its own (PDB: 6zct) has been solved for SARS-CoV-2. Multiple structures of the Nsp10-Nsp16 complex are available; with the highest resolution structure being PDB: 6w4h. Structures of Nsp10 in complex with Nsp14 currently only exist for the SARS-CoV proteins (PDB entries 5c8s, 5c8t, 5c8u, and 5nfy); however, with 97% and 95% sequence identity to SARS-CoV-2, respectively, this model can inform research on the SARS-CoV-2 enzymes as well. All the above structural information was based on publications on the structures currently available for SARS-CoV (PDBID: 2fyg, 2g9t, and 2ga6) [6][7]. Current online information available for the SARS-CoV-2 Nsp10 (PDB: 6zct) can be found at the maxiv website[8]. See alsoCoronavirus_Disease 2019 (COVID-19)
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References
- ↑ 1.0 1.1 Modeling of the SARS-COV-2 Genome
- ↑ 2.0 2.1 Zhang C, Zheng W, Huang X, Bell EW, Zhou X, Zhang Y. Protein Structure and Sequence Reanalysis of 2019-nCoV Genome Refutes Snakes as Its Intermediate Host and the Unique Similarity between Its Spike Protein Insertions and HIV-1. J Proteome Res. 2020 Apr 3;19(4):1351-1360. doi: 10.1021/acs.jproteome.0c00129., Epub 2020 Mar 24. PMID:32200634 doi:http://dx.doi.org/10.1021/acs.jproteome.0c00129
- ↑ Ferron F, Subissi L, Silveira De Morais AT, Le NTT, Sevajol M, Gluais L, Decroly E, Vonrhein C, Bricogne G, Canard B, Imbert I. Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA. Proc Natl Acad Sci U S A. 2017 Dec 26. pii: 1718806115. doi:, 10.1073/pnas.1718806115. PMID:29279395 doi:http://dx.doi.org/10.1073/pnas.1718806115
- ↑ Bouvet M, Imbert I, Subissi L, Gluais L, Canard B, Decroly E. RNA 3'-end mismatch excision by the severe acute respiratory syndrome coronavirus nonstructural protein nsp10/nsp14 exoribonuclease complex. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9372-7. doi:, 10.1073/pnas.1201130109. Epub 2012 May 25. PMID:22635272 doi:http://dx.doi.org/10.1073/pnas.1201130109
- ↑ Romano M, Ruggiero A, Squeglia F, Maga G, Berisio R. A Structural View of SARS-CoV-2 RNA Replication Machinery: RNA Synthesis, Proofreading and Final Capping. Cells. 2020 May 20;9(5). pii: cells9051267. doi: 10.3390/cells9051267. PMID:32443810 doi:http://dx.doi.org/10.3390/cells9051267
- ↑ 6.0 6.1 <pmid 16873246
- ↑ 7.0 7.1 <pmid 16873247
- ↑ [1]
