9ati

Structural highlights

Function

R1A_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]. Also able to bind an ADP-ribose-1-phosphate (ADRP).[UniProtKB:P0C6X7][PROSITE-ProRule:PRU00772] 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] May participate in viral replication by acting as a ssRNA-binding protein.[UniProtKB:P0C6X7] 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]

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. ↑ Dampalla CS, Kim Y, Zabiegala A, Howard DJ, Nguyen HN, Madden TK, Thurman HA, Cooper A, Liu L, Battaile KP, Lovell S, Chang KO, Groutas WC. Structure-Guided Design of Potent Coronavirus Inhibitors with a 2-Pyrrolidone Scaffold: Biochemical, Crystallographic, and Virological Studies. J Med Chem. 2024 Jul 2. PMID:38953866 doi:10.1021/acs.jmedchem.4c00551