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From Proteopedia
CryoEM structure of the Chikungunya virus nsP1 complex
Structural highlights
Function[POLN_CHIKS] P123 is short-lived polyproteins, accumulating during early stage of infection. It localizes the viral replication complex to the cytoplasmic surface of modified endosomes and lysosomes. By interacting with nsP4, it starts viral genome replication into antigenome. After these early events, P123 is cleaved sequentially into nsP1, nsP2 and nsP3. This sequence of delayed processing would allow correct assembly and membrane association of the RNA polymerase complex (By similarity). nsP1 is a cytoplasmic capping enzyme. This function is necessary since all viral RNAs are synthesized in the cytoplasm, and host capping enzymes are restricted to the nucleus. The enzymatic reaction involves a covalent link between 7-methyl-GMP and nsP1, whereas eukaryotic capping enzymes form a covalent complex only with GMP. nsP1 capping would consist in the following reactions: GTP is first methylated and then forms the m7GMp-nsP1 complex, from which 7-methyl-GMP complex is transferred to the mRNA to create the cap structure. Palmitoylated nsP1 is remodeling host cell cytoskeleton, and induces filopodium-like structure formation at the surface of the host cell (By similarity). nsP2 has two separate domain with different biological activities. The N-terminal section is part of the RNA polymerase complex and has RNA trisphosphatase and RNA helicase activity. The C-terminal section harbors a protease that specifically cleaves and releases the four mature proteins (By similarity). Also inhibits cellular transcription by inducing rapid degradation of POLR2A, a catalytic subunit of the RNAPII complex. The resulting inhibition of cellular protein synthesis serves to ensure maximal viral gene expression and to evade host immune response. nsP3 is essential for minus strand and subgenomic 26S mRNA synthesis (By similarity). nsP4 is an RNA dependent RNA polymerase. It replicates genomic and antigenomic RNA by recognizing replications specific signals. Transcribes also a 26S subgenomic mRNA by initiating RNA synthesis internally on antigenomic RNA. This 26S mRNA codes for structural proteins (By similarity). Publication Abstract from PubMedPositive-sense single-stranded RNA viruses, such as coronaviruses, flaviviruses and alphaviruses, carry out transcription and replication inside virus-induced membranous organelles within host cells(1-7). The remodelling of the host-cell membranes for the formation of these organelles is coupled to the membrane association of viral replication complexes and to RNA synthesis. These viral niches allow for the concentration of metabolites and proteins for the synthesis of viral RNA, and prevent the detection of this RNA by the cellular innate immune system(8). Here we present the cryo-electron microscopy structure of non-structural protein 1 (nsP1) of the alphavirus chikungunya virus, which is responsible for RNA capping and membrane binding of the viral replication machinery. The structure shows the enzyme in its active form, assembled in a monotopic membrane-associated dodecameric ring. The structure reveals the structural basis of the coupling between membrane binding, oligomerization and allosteric activation of the capping enzyme. The stoichiometry-with 12 active sites in a single complex-redefines viral replication complexes as RNA synthesis reactors. The ring shape of the complex implies it has a role in controlling access to the viral organelle and ensuring the exit of properly capped viral RNA. Our results provide high-resolution information about the membrane association of the replication machinery of positive-sense single-stranded RNA viruses, and open up avenues for the further characterization of viral replication on cell membranes and the generation of antiviral agents. Capping pores of alphavirus nsP1 gate membranous viral replication factories.,Jones R, Bragagnolo G, Arranz R, Reguera J Nature. 2020 Dec 16. pii: 10.1038/s41586-020-3036-8. doi:, 10.1038/s41586-020-3036-8. PMID:33328629[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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