6r0g
Getah virus macro domain in complex with ADPr, pose 2
Structural highlights
FunctionPOLN_GETV Inactive precursor of the viral replicase, which is activated by cleavages carried out by the viral protease nsP2.[UniProtKB:Q8JUX6] The early replication complex formed by the polyprotein P123 and nsP4 synthesizes minus-strand RNAs (By similarity). As soon P123 is cleaved into mature proteins, the plus-strand RNAs synthesis begins (By similarity).[UniProtKB:P03317] The early replication complex formed by the polyprotein P123' and nsP4 synthesizes minus-strand RNAs (Probable). Polyprotein P123' is a short-lived polyprotein that accumulates during early stage of infection (Probable). As soon P123' is cleaved into mature proteins, the plus-strand RNAs synthesis begins (Probable). Cytoplasmic capping enzyme that catalyzes two virus-specific reactions: methyltransferase and nsP1 guanylyltransferase (By similarity). mRNA-capping is necessary since all viral RNAs are synthesized in the cytoplasm, and host capping enzymes are restricted to the nucleus (Probable). The enzymatic reaction involves a covalent link between 7-methyl-GMP and nsP1, whereas eukaryotic capping enzymes form a covalent complex only with GMP (By similarity). nsP1 capping consists in the following reactions: GTP is first methylated into 7-methyl-GMP and then is covalently linked to nsP1 to form the m7GMp-nsP1 complex from which 7-methyl-GMP complex is transferred to the mRNA to create the cap structure (By similarity). NsP1 is needed for the initiation of the minus-strand RNAs synthesis (By similarity). Probably serves as a membrane anchor for the replication complex composed of nsP1-nsP4 (By similarity). Palmitoylated nsP1 is remodeling host cell cytoskeleton, and induces filopodium-like structure formation at the surface of the host cell (By similarity).[UniProtKB:P03317][UniProtKB:P08411][UniProtKB:Q8JUX6] Multifunctional protein whose N-terminus is part of the RNA polymerase complex and displays NTPase, RNA triphosphatase and helicase activities (By similarity). NTPase and RNA triphosphatase are involved in viral RNA capping and helicase keeps a check on the dsRNA replication intermediates (By similarity). The C-terminus harbors a protease that specifically cleaves the polyproteins and releases the mature proteins (By similarity). Required for the shutoff of minus-strand RNAs synthesis (By similarity). Specifically inhibits the host IFN response by promoting the nuclear export of host STAT1 (By similarity). Also inhibits host transcription by inducing rapid proteasome-dependent degradation of POLR2A, a catalytic subunit of the RNAPII complex (By similarity). The resulting inhibition of cellular protein synthesis serves to ensure maximal viral gene expression and to evade host immune response (By similarity).[UniProtKB:P03317][UniProtKB:P08411][UniProtKB:Q8JUX6] Seems to be essential for minus-strand RNAs and subgenomic 26S mRNAs synthesis (By similarity). Displays mono-ADP-ribosylhydrolase activity (Probable). ADP-ribosylation is a post-translational modification that controls various processes of the host cell and the virus probably needs to revert it for optimal viral replication (Probable). Binds proteins of FXR family and sequesters them into the viral RNA replication complexes thereby inhibiting the formation of host stress granules on viral mRNAs (Probable). The nsp3'-FXR complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes, thanks to the ability of FXR family members to self-assemble and bind DNA (Probable).[UniProtKB:P03317] Seems to be essential for minus-strand RNAs and subgenomic 26S mRNAs synthesis (By similarity). Displays mono-ADP-ribosylhydrolase activity (By similarity). ADP-ribosylation is a post-translantional modification that controls various processes of the host cell and the virus probably needs to revert it for optimal viral replication (By similarity). Binds proteins of G3BP family and sequesters them into the viral RNA replication complexes thereby inhibiting the formation of host stress granules on viral mRNAs (By similarity). The nsp3-G3BP complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes, thanks to the ability of G3BP family members to self-assemble and bind DNA (By similarity).[UniProtKB:P03317][UniProtKB:Q8JUX6] RNA dependent RNA polymerase (By similarity). Replicates genomic and antigenomic RNA by recognizing replications specific signals. The early replication complex formed by the polyprotein P123 and nsP4 synthesizes minus-strand RNAs (By similarity). The late replication complex composed of fully processed nsP1-nsP4 is responsible for the production of genomic and subgenomic plus-strand RNAs (By similarity). The core catalytic domain of nsP4 also possesses terminal adenylyltransferase (TATase) activity that is probably involved in maintenance and repair of the poly(A) tail, an element required for replication of the viral genome (By similarity).[UniProtKB:P03317] Publication Abstract from PubMedAlphaviruses are (re-)emerging arboviruses of public health concern. The nsP3 gene product is one of the key players during viral replication. NsP3 comprises three domains: a macro domain, a zinc-binding domain and a hypervariable region. The macro domain is essential at both early and late stages of the replication cycle through ADP-ribose (ADPr) binding and de-ADP-ribosylation of host proteins. However, both its specific role and the precise molecular mechanism of de-ADP-ribosylation across specific viral families remains to be elucidated. Here we investigate by X-ray crystallography the mechanism of ADPr reactivity in the active site of Getah virus macro domain, which displays a peculiar substitution of one of the conserved residues in the catalytic loop. ADPr adopts distinct poses including a covalent bond between the C1 of the ADPr and a conserved Togaviridae-specific cysteine. These different poses observed for ADPr may represent snapshots of the de-ADP-ribosylation mechanism, highlighting residues to be further characterised. Snapshots of ADP-ribose bound to Getah virus macro domain reveal an intriguing choreography.,Ferreira-Ramos AS, Sulzenbacher G, Canard B, Coutard B Sci Rep. 2020 Sep 2;10(1):14422. doi: 10.1038/s41598-020-70870-w. PMID:32879358[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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