SARS-CoV-2 protein NSP1
From Proteopedia
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| - | < | + | <StructureSection load='7K3N' size='350' side='right' caption='SARS-CoV-2 protein NS1 (PDB entry [[7k3n]])' scene='84/842015/7k3n/1'> |
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== Function == | == Function == | ||
| + | The '''non-structural protein nsp1''', also referred to as '''leader protein''', '''host translation inhibitor''' or '''host shutoff factor''', binds to the 40S ribosomal subunit and the 80S ribosome<ref name="Schubert"> PMID: 32908316 </ref>. It contains 180 amino acids<ref name="Yoshimoto"> PMID: 32447571 </ref>, is encoded on the ORF1a<ref name="Konkolova"> PMID: 32535228 </ref> and is expressed by all betacoronaviruses<ref name="Menezes"> PMID: 32657643</ref>. | ||
| + | By binding to the mRNA channel of the 40S ribosomal subunit, nsp1 shuts down the host protein production. A result is the suppression of a large part of the innate immune system that depends on the translation of antiviral defense factors, like interferons (IFN), other proinflammatory cytokines and antiviral IFN-stimulated genes<ref name="Thoms"> PMID: 32680882 </ref>. | ||
| - | The non-structural protein nsp1, also referred to as leader protein, host translation inhibitor or host shutoff factor, binds to the 40S ribosomal subunit and the 80S ribosome<ref name="Schubert"> PMID: 32908316 </ref>. It contains 180 amino acids<ref name="Yoshimoto"> PMID: 32447571 </ref>, is encoded on the ORF1a<ref name="Konkolova"> PMID: 32535228 </ref> and is expressed by all betacoronaviruses<ref name="Menezes"> PMID: 32657643</ref>. | ||
| - | By binding to the mRNA channel of the 40S ribosomal subunit, nsp1 shuts down the host protein production. A result is the suppression of a large part of the innate immune system that depends on the translation of antiviral defense factors, like interferons (IFN), other proinflammatory cytokines and antiviral IFN-stimulated genes<ref name="Thoms"> PMID: 32680882 </ref>. | ||
Additionally, binding of nsp1 of SARS-CoV to the 40S ribosomal subunit induces the endonucleolytic cleavage of only the host mRNA to suppress the expression of host genes<ref name="Huang"> PMID: 22174690</ref>. | Additionally, binding of nsp1 of SARS-CoV to the 40S ribosomal subunit induces the endonucleolytic cleavage of only the host mRNA to suppress the expression of host genes<ref name="Huang"> PMID: 22174690</ref>. | ||
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==Structure== | ==Structure== | ||
| - | Nsp1 consists of a N-terminal domain, a C-terminal domain, and a 20-amino acid long unstructured linker, which flexibly connects the two<ref name="Schubert"/>. The C-terminal domain contains the two α-helices (α1: 154-160, α2: 166-179) and a short loop, which holds the conserved KH-motif (K164 and H165)<ref name="Thoms"/>. | + | The 3D structure of Nsp1<ref name="Zhang"> PMID: 32198291</ref><ref name="Semper"> PMID: 33319167</ref> consists of a N-terminal domain, a C-terminal domain, and a 20-amino acid long unstructured linker, which flexibly connects the two<ref name="Schubert"/>. The C-terminal domain contains the two α-helices (α1: 154-160, α2: 166-179) and a short loop, which holds the conserved KH-motif (K164 and H165)<ref name="Thoms"/>. |
The C-terminal domain is known to bind inside the mRNA entry channel of the 40S ribosomal subunit. There its α-helix α1 interacts with the ribosomal proteins uS3 and uS5 of 40S, the KH motif with the rRNA helix h18, and α2 with h18 and uS5. Through hydrophobic interactions both α-helices stabilize each other. The surface charge as well as the shape of the C-terminal domain match with the nsp1 interacting parts of 40S, and overlap the mRNA path<ref name="Thoms"/>. While the C-terminal domain is bound to the 40S mRNA channel, the N-terminal domain can move within a ~60 Å radius from its connection to the C-terminal domain<ref name="Schubert"/>. | The C-terminal domain is known to bind inside the mRNA entry channel of the 40S ribosomal subunit. There its α-helix α1 interacts with the ribosomal proteins uS3 and uS5 of 40S, the KH motif with the rRNA helix h18, and α2 with h18 and uS5. Through hydrophobic interactions both α-helices stabilize each other. The surface charge as well as the shape of the C-terminal domain match with the nsp1 interacting parts of 40S, and overlap the mRNA path<ref name="Thoms"/>. While the C-terminal domain is bound to the 40S mRNA channel, the N-terminal domain can move within a ~60 Å radius from its connection to the C-terminal domain<ref name="Schubert"/>. | ||
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== See also == | == See also == | ||
| - | [[Coronavirus_Disease 2019 (COVID-19)]] | + | [[Coronavirus_Disease 2019 (COVID-19)]]<br> |
| + | [[SARS-CoV-2_virus_proteins]]<br> | ||
| + | [[COVID-19 AlphaFold2 Models]] | ||
__NOTOC__ | __NOTOC__ | ||
| - | </ | + | </StructureSection> |
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
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References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Schubert K, Karousis ED, Jomaa A, Scaiola A, Echeverria B, Gurzeler LA, Leibundgut M, Thiel V, Muhlemann O, Ban N. SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation. Nat Struct Mol Biol. 2020 Sep 9. pii: 10.1038/s41594-020-0511-8. doi:, 10.1038/s41594-020-0511-8. PMID:32908316 doi:http://dx.doi.org/10.1038/s41594-020-0511-8
- ↑ 2.0 2.1 Yoshimoto FK. The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the Cause of COVID-19. Protein J. 2020 Jun;39(3):198-216. doi: 10.1007/s10930-020-09901-4. PMID:32447571 doi:http://dx.doi.org/10.1007/s10930-020-09901-4
- ↑ Konkolova E, Klima M, Nencka R, Boura E. Structural analysis of the putative SARS-CoV-2 primase complex. J Struct Biol. 2020 Aug 1;211(2):107548. doi: 10.1016/j.jsb.2020.107548. Epub, 2020 Jun 11. PMID:32535228 doi:http://dx.doi.org/10.1016/j.jsb.2020.107548
- ↑ 4.0 4.1 de Lima Menezes G, da Silva RA. Identification of potential drugs against SARS-CoV-2 non-structural protein 1 (nsp1). J Biomol Struct Dyn. 2020 Jul 13:1-11. doi: 10.1080/07391102.2020.1792992. PMID:32657643 doi:http://dx.doi.org/10.1080/07391102.2020.1792992
- ↑ 5.0 5.1 5.2 Thoms M, Buschauer R, Ameismeier M, Koepke L, Denk T, Hirschenberger M, Kratzat H, Hayn M, Mackens-Kiani T, Cheng J, Straub JH, Sturzel CM, Frohlich T, Berninghausen O, Becker T, Kirchhoff F, Sparrer KMJ, Beckmann R. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science. 2020 Jul 17. pii: science.abc8665. doi: 10.1126/science.abc8665. PMID:32680882 doi:http://dx.doi.org/10.1126/science.abc8665
- ↑ Huang C, Lokugamage KG, Rozovics JM, Narayanan K, Semler BL, Makino S. SARS coronavirus nsp1 protein induces template-dependent endonucleolytic cleavage of mRNAs: viral mRNAs are resistant to nsp1-induced RNA cleavage. PLoS Pathog. 2011 Dec;7(12):e1002433. doi: 10.1371/journal.ppat.1002433. Epub, 2011 Dec 8. PMID:22174690 doi:http://dx.doi.org/10.1371/journal.ppat.1002433
- ↑ Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfeld R. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors. Science. 2020 Mar 20. pii: science.abb3405. doi: 10.1126/science.abb3405. PMID:32198291 doi:http://dx.doi.org/10.1126/science.abb3405
- ↑ Semper C, Watanabe N, Savchenko A. Structural characterization of nonstructural protein 1 from SARS-CoV-2. iScience. 2021 Jan 22;24(1):101903. doi: 10.1016/j.isci.2020.101903. Epub 2020, Dec 7. PMID:33319167 doi:http://dx.doi.org/10.1016/j.isci.2020.101903
- ↑ 9.0 9.1 Shi M, Wang L, Fontana P, Vora S, Zhang Y, Fu TM, Lieberman J, Wu H. SARS-CoV-2 Nsp1 suppresses host but not viral translation through a bipartite mechanism. bioRxiv. 2020 Sep 18. doi: 10.1101/2020.09.18.302901. PMID:32995777 doi:http://dx.doi.org/10.1101/2020.09.18.302901
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