8ig6

Structural highlights

Function

R1AB_MERS1 The replicase polyprotein of coronaviruses is a multifunctional protein: it contains the activities necessary for the transcription of negative stranded RNA, leader RNA, subgenomic mRNAs and progeny virion RNA as well as proteinases responsible for the cleavage of the polyprotein into functional products.[UniProtKB:P0C6X7] Promotes the degradation of host mRNAs by inducing an endonucleolytic RNA cleavage in template mRNAs, and inhibits of host mRNA translation, a function that is separable from its RNA cleavage activity. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response.^[1] May play a role in the modulation of host cell survival signaling pathway by interacting with host PHB and PHB2. Indeed, these two proteins play a role in maintaining the functional integrity of the mitochondria and protecting cells from various stresses.[UniProtKB:P0C6X7] Responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. Participates, together with nsp4, in the assembly of virally induced cytoplasmic double-membrane vesicles necessary for viral replication. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3. Prevents also host NF-kappa-B. signaling.[UniProtKB:P0C6X7]^[2] Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication.[UniProtKB:P0C6X7] Cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN] (By similarity). May cleave human NLRP1 in lung epithelial cells, thereby activating the NLRP1 inflammasome pathway (PubMed:35594856). Also able to bind an ADP-ribose-1-phosphate (ADRP) (By similarity).[UniProtKB:P0C6X7][PROSITE-ProRule:PRU00772]^[3] Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic. Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes.[UniProtKB:P0C6X7] Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7] Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7] Forms a primer, NSP9-pU, which is utilized by the polymerase for the initiation of RNA chains. Interacts with ribosome signal recognition particle RNA (SRP). Together with NSP8, suppress protein integration into the cell membrane, thereby disrupting host immune defenses.[UniProtKB:P0DTD1] Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities. Therefore plays an essential role in viral mRNAs cap methylation.[UniProtKB:P0C6X7] RNA-directed RNA polymerase that catalyzes the transcription of viral genomic and subgenomic RNAs. Acts in complex with nsp7 and nsp8 to transcribe both the minus and positive strands of genomic RNA. The kinase-like NiRAN domain of NSP12 attaches one or more nucleotides to the amino terminus of NSP9, forming a covalent RNA-protein intermediate that serves as transcription/replication primer. Subgenomic RNAs (sgRNAs) are formed by discontinuous transcription: The polymerase has the ability to pause at transcription-regulating sequences (TRS) and jump to the leader TRS, resulting in a major deletion. This creates a series of subgenomic RNAs that are replicated, transcribed and translated. In addition, Nsp12 is a subunit of the viral RNA capping enzyme that catalyzes the RNA guanylyltransferase reaction for genomic and sub-genomic RNAs. Subsequently, the NiRAN domain transfers RNA to GDP, and forms the core cap structure GpppA-RNA.[UniProtKB:P0DTD1] Multi-functional protein with a zinc-binding domain in N-terminus displaying RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Activity of helicase is dependent on magnesium.[UniProtKB:P0C6X7] Plays a role in viral RNA synthesis through two distinct activities: an N7-guanine methyltransferase activity involved in the formation of the cap structure GpppA-RNA; a proofreading exoribonuclease for RNA replication that reduces the sensitivity of the virus to RNA mutagens. This activity acts on both ssRNA and dsRNA in a 3'-5' direction.[UniProtKB:P0C6X7] Plays a role in viral transcription/replication and prevents the simultaneous activation of host cell dsRNA sensors, such as MDA5/IFIH1, OAS, and PKR (By similarity). Acts by degrading the 5'-polyuridines generated during replication of the poly(A) region of viral genomic and subgenomic RNAs. Catalyzes a two-step reaction in which a 2'3'-cyclic phosphate (2'3'-cP) is first generated by 2'-O transesterification, which is then hydrolyzed to a 3'-phosphate (3'-P) (By similarity). If not degraded, poly(U) RNA would hybridize with poly(A) RNA tails and activate host dsRNA sensors (By similarity).[UniProtKB:P0C6X7] Methyltransferase that mediates mRNA cap 2'-O-ribose methylation to the 5'-cap structure of viral mRNAs. N7-methyl guanosine cap is a prerequisite for binding of nsp16. Therefore plays an essential role in viral mRNAs cap methylation which is essential to evade immune system.[UniProtKB:P0C6X7]

References

1. ↑ Lokugamage KG, Narayanan K, Nakagawa K, Terasaki K, Ramirez SI, Tseng CT, Makino S. Middle East Respiratory Syndrome Coronavirus nsp1 Inhibits Host Gene Expression by Selectively Targeting mRNAs Transcribed in the Nucleus while Sparing mRNAs of Cytoplasmic Origin. J Virol. 2015 Nov;89(21):10970-81. doi: 10.1128/JVI.01352-15. Epub 2015 Aug 26. PMID:26311885 doi:http://dx.doi.org/10.1128/JVI.01352-15
2. ↑ Baez-Santos YM, Mielech AM, Deng X, Baker S, Mesecar AD. Catalytic function and substrate specificity of the papain-like protease domain of nsp3 from the Middle East respiratory syndrome coronavirus. J Virol. 2014 Nov;88(21):12511-27. doi: 10.1128/JVI.01294-14. Epub 2014 Aug 20. PMID:25142582 doi:http://dx.doi.org/10.1128/JVI.01294-14
3. ↑ Planès R, Pinilla M, Santoni K, Hessel A, Passemar C, Lay K, Paillette P, Valadão AC, Robinson KS, Bastard P, Lam N, Fadrique R, Rossi I, Pericat D, Bagayoko S, Leon-Icaza SA, Rombouts Y, Perouzel E, Tiraby M, Zhang Q, Cicuta P, Jouanguy E, Neyrolles O, Bryant CE, Floto AR, Goujon C, Lei FZ, Martin-Blondel G, Silva S, Casanova JL, Cougoule C, Reversade B, Marcoux J, Ravet E, Meunier E. Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells. Mol Cell. 2022 Jul 7;82(13):2385-2400.e9. PMID:35594856 doi:10.1016/j.molcel.2022.04.033
4. ↑ Lin C, Zhu Z, Jiang H, Zou X, Zeng X, Wang J, Zeng P, Li W, Zhou X, Zhang J, Wang Q, Li J. Structural Basis for Coronaviral Main Proteases Inhibition by the 3CLpro Inhibitor GC376. J Mol Biol. 2024 Mar 15;436(6):168474. PMID:38311236 doi:10.1016/j.jmb.2024.168474