6gpg

Structure of the RIG-I Singleton-Merten syndrome variant C268FStructure of the RIG-I Singleton-Merten syndrome variant C268F

Structural highlights 6gpg is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , Activity: RNA helicase, with EC number 3.6.4.13 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [DDX58_HUMAN] Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and proinflammatory cytokines. Its ligands include: 5'-triphosphorylated ssRNA and dsRNA and short dsRNA (<1 kb in length). In addition to the 5'-triphosphate moiety, blunt-end base pairing at the 5'-end of the RNA is very essential. Overhangs at the non-triphosphorylated end of the dsRNA RNA have no major impact on its activity. A 3'overhang at the 5'triphosphate end decreases and any 5'overhang at the 5' triphosphate end abolishes its activity. Upon ligand binding it associates with mitochondria antiviral signaling protein (MAVS/IPS1) which activates the IKK-related kinases: TBK1 and IKBKE which phosphorylate interferon regulatory factors: IRF3 and IRF7 which in turn activate transcription of antiviral immunological genes, including interferons (IFNs); IFN-alpha and IFN-beta. Detects both positive and negative strand RNA viruses including members of the families Paramyxoviridae: Human respiratory syncytial virus and measles virus (MeV), Rhabdoviridae: vesicular stomatitis virus (VSV), Orthomyxoviridae: influenza A and B virus, Flaviviridae: Japanese encephalitis virus (JEV), hepatitis C virus (HCV), dengue virus (DENV) and west Nile virus (WNV). It also detects rotavirus and reovirus. Also involved in antiviral signaling in response to viruses containing a dsDNA genome such as Epstein-Barr virus (EBV). Detects dsRNA produced from non-self dsDNA by RNA polymerase III, such as Epstein-Barr virus-encoded RNAs (EBERs). May play important roles in granulocyte production and differentiation, bacterial phagocytosis and in the regulation of cell migration. Publication Abstract from PubMed The innate immune sensor RIG-I detects cytosolic viral RNA and requires a conformational change caused by both ATP and RNA binding to induce an active signalling state and to trigger an immune response. Previously, we showed that ATP hydrolysis removes RIG-I from lower affinity self-RNAs (Lassig et al., 2015), revealing how ATP turnover helps RIGI distinguish viral from self-RNA and explaining why a mutation in a motif that slows down ATP hydrolysis causes the autoimmune disease Singleton-Merten syndrome (SMS). Here we show that a different, mechanistically unexplained SMS variant, C268F, localised in the ATP binding P-loop, can signal independently of ATP but still dependent on RNA. The structure in complex with dsRNA reveals that C268F helps induce a similar structural conformation in RIG-I than ATP. Our results uncover an unexpected mechanism how a mutation in a P-loop ATPase can induce a gain-of-function ATP state in the absence of ATP. Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants.,Lassig C, Lammens K, Gorenflos Lopez JL, Michalski S, Fettscher O, Hopfner KP Elife. 2018 Jul 26;7. pii: 38958. doi: 10.7554/eLife.38958. PMID:30047865 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 6gpg, resolution 2.89Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image