SARS-CoV-2 protein NSP1
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
<SX viewer='molstar' load='' size='340' side='right' caption='' scene='83/839266/Covid-2_nsp1/1'> | <SX viewer='molstar' load='' size='340' side='right' caption='' scene='83/839266/Covid-2_nsp1/1'> | ||
| - | + | '''Non-structural protein 1 (nsp1)/ Leader protein/ Host translation inhibitor/ Host shutoff factor''' | |
| + | |||
== Function == | == Function == | ||
| - | '''Host translation inhibitor nsp1.''' | ||
| - | Inhibits host translation by interacting with the 40S ribosomal subunit. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation. Viral mRNAs are not susceptible to nsp1-mediated endonucleolytic RNA cleavage thanks to the presence of a 5'-end leader sequence and are therefore protected from degradation. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response.<ref>[https://zhanglab.ccmb.med.umich.edu/COVID-19/ Modeling of the SARS-COV-2 Genome]</ref><ref>pmid 32200634</ref> | ||
| - | == Disease == | + | 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>. | ||
| + | |||
| + | ==Disease== | ||
| + | The global COVID-19 pandemic, which started in 2019, is caused by the SARS-CoV-2. | ||
| + | |||
| + | ==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 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"/>. | ||
| + | |||
| + | To maintain the translation of the viral mRNA, the virus has to circumvent the translational blockage, which is induced by the binding of nsp1 to the 40S mRNA channel<ref name="Schubert"/>. How this is accomplished is a matter of debate. | ||
| + | One suggested way is by using the interaction of the N-terminal domain and the 5’ untranslated region (5’ UTR) of the SARS-CoV-2 mRNA<ref name="Shi"> PMID: 32995777</ref>. This 5’ UTR is shown to promote translation initiation and to have a complex secondary structure that is conserved among most coronaviruses<ref name="Schubert"/>. As the lengthening of the linker in nsp1 was shown to result in a reduced ability of escaping the translational inhibition, the incompatibility of the simultaneous interaction with 40S and the viral 5’ UTR is suggested to be of steric nature<ref name="Shi"/> | ||
| + | Another proposal is that the level of nsp1 blocked ribosomes is kept so high, that the remaining unblocked ones will translate the 5’UTR containing viral mRNA with higher efficiency than the cellular mRNA<ref name="Schubert"/>. | ||
| - | == | + | ==Variations== |
| + | Compared to the amino acid sequence of SARS-CoV, the SARS-CoV-2 sequence of nsp1 has 28 amino acid substitutions, resulting in a sequence identity of 84.4% and a sequence similarity of 93.3%<ref name="Yoshimoto"/>. | ||
| - | == | + | ==Relevance== |
| + | Nsp1 is a probably major virulence factor and might therefore be an interesting drug target in association with drugs targeting other parts of the virus<ref name="Menezes"/>. | ||
== See also == | == See also == | ||
Revision as of 22:32, 14 November 2020
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
- ↑ 7.0 7.1 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
Proteopedia Page Contributors and Editors (what is this?)
Joel L. Sussman, Michal Harel, Lea C. von Soosten, Jaime Prilusky
