6lpa
The nsp1 protein of a new porcine coronavirus
Structural highlights
FunctionA0A2P1G738_9ALPC Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter.[ARBA:ARBA00002928] Nsp9 is a ssRNA-binding protein.[ARBA:ARBA00003140] The exoribonuclease acts on both ssRNA and dsRNA in a 3' to 5' direction.[ARBA:ARBA00003315] The papain-like proteinase 1 (PLP1) and papain-like proteinase 2 (PLP2) are responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PLP2 possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. PLP2 also antagonizes innate immune induction of type I interferon by blocking the nuclear translocation of host IRF-3.[ARBA:ARBA00025562] 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.[ARBA:ARBA00003368] Publication Abstract from PubMedNon-structural protein 1 (nsp1) is only characterized in alphacoronaviruses (alpha-CoVs) and betacoronaviruses (beta-CoVs). There have been extensive researches on how the beta-CoVs nsp1 regulates viral virulence by inhibiting host protein synthesis, but the regulatory mechanism of the alpha-CoVs nsp1 is still unclear. Here, we report the 2.1-A full-length crystal structure of nsp1 in emerging porcine SADS-CoV and the 1.8-A full-length crystal structure of nsp1 in the highly lethal cat FIPV. Although they belong to different subtypes of alpha-CoVs, these viruses all have a bucket-shaped fold composed of six beta-sheets, similar to the crystal structure of PEDV and TGEV nsp1. Comparing the above four structures, we found that the structure of alpha-CoVs nsp1 in the same subtype was more conserved. We then selected mammalian cells that were treated with SADS-CoV and FIPV nsp1 for RNA sequencing analysis and found that nsp1 had a specific inhibitory effect on interferon (IFN) and cell cycle genes. Using the Renilla luciferase (Rluc) assay and Western blotting, we confirmed that seven representative alpha-CoVs nsp1s could significantly inhibit the phosphorylation of STAT1-S727 and interfere with the effect of IFN-I. Moreover, the cell cycle experiment confirmed that alpha-CoVs nsp1 could encourage host cells to stay in the G0/G1 phase. Based on these findings, we not only greatly improved the crystal structure data on alpha-CoVs nsp1, but we also speculated that alpha-CoVs nsp1 regulated host proliferation and immune evasion-related biological functions by inhibiting the synthesis of host proteins, thus creating an environment conducive to the virus. Structural and Biological Basis of Alphacoronavirus nsp1 Associated with Host Proliferation and Immune Evasion.,Shen Z, Yang Y, Yang S, Zhang G, Xiao S, Fu ZF, Peng G Viruses. 2020 Jul 28;12(8). pii: v12080812. doi: 10.3390/v12080812. PMID:32731335[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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