7bai

Structure of RIG-I CTD (I875A) bound to p-RNA

spinqualitylabelsall models 7bai, resolution 3.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7bai is a 6 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.4Å Ligands: GDP, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease RIGI_HUMAN Singleton-Merten dysplasia. The disease is caused by variants affecting the gene represented in this entry. Function RIGI_HUMAN Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and pro-inflammatory cytokines (PubMed:15208624, PubMed:15708988, PubMed:16125763, PubMed:16127453, PubMed:16153868, PubMed:17190814, PubMed:18636086, PubMed:19122199, PubMed:19211564, PubMed:24366338, PubMed:28469175, PubMed:29117565, PubMed:31006531, PubMed:34935440, PubMed:35263596, PubMed:36793726). Forms a ribonucleoprotein complex with viral RNAs on which it homooligomerizes to form filaments (PubMed:15208624, PubMed:15708988). The homooligomerization allows the recruitment of RNF135 an E3 ubiquitin-protein ligase that activates and amplifies the RIG-I-mediated antiviral signaling in an RNA length-dependent manner through ubiquitination-dependent and -independent mechanisms (PubMed:28469175, PubMed:31006531). Upon activation, associates with mitochondria antiviral signaling protein (MAVS/IPS1) that activates the IKK-related kinases TBK1 and IKBKE which in turn phosphorylate the interferon regulatory factors IRF3 and IRF7, activating transcription of antiviral immunological genes including the IFN-alpha and IFN-beta interferons (PubMed:28469175, PubMed:31006531). Ligands include 5'-triphosphorylated ssRNAs and dsRNAs but also short dsRNAs (<1 kb in length) (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). In addition to the 5'-triphosphate moiety, blunt-end base pairing at the 5'-end of the RNA is very essential (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). Overhangs at the non-triphosphorylated end of the dsRNA RNA have no major impact on its activity (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). A 3'overhang at the 5'triphosphate end decreases and any 5'overhang at the 5' triphosphate end abolishes its activity (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). 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) (PubMed:21616437, PubMed:21884169). It also detects rotaviruses and reoviruses (PubMed:21616437, PubMed:21884169). Detects and binds to SARS-CoV-2 RNAs which is inhibited by m6A RNA modifications (Ref.70). Also involved in antiviral signaling in response to viruses containing a dsDNA genome such as Epstein-Barr virus (EBV) (PubMed:19631370). 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. [REFERENCE:70] Publication Abstract from PubMed RIG-I is a cytosolic receptor of viral RNA essential for the immune response to numerous RNA viruses. Accordingly, RIG-I must sensitively detect viral RNA yet tolerate abundant self-RNA species. The basic binding cleft and an aromatic amino acid of the RIG-I C-terminal domain(CTD) mediate high-affinity recognition of 5'triphosphorylated and 5'base-paired RNA(dsRNA). Here, we found that, while 5'unmodified hydroxyl(OH)-dsRNA demonstrated residual activation potential, 5'-monophosphate(5'p)-termini, present on most cellular RNAs, prevented RIG-I activation. Determination of CTD/dsRNA co-crystal structures and mutant activation studies revealed that the evolutionarily conserved I875 within the CTD sterically inhibits 5'p-dsRNA binding. RIG-I(I875A) was activated by both synthetic 5'p-dsRNA and endogenous long dsRNA within the polyA-rich fraction of total cellular RNA. RIG-I(I875A) specifically interacted with long, polyA-bearing, mitochondrial(mt) RNA, and depletion of mtRNA from total RNA abolished its activation. Altogether, our study demonstrates that avoidance of 5'p-RNA recognition is crucial to prevent mtRNA-triggered RIG-I-mediated autoinflammation. A conserved isoleucine in the binding pocket of RIG-I controls immune tolerance to mitochondrial RNA.,de Regt AK, Anand K, Ciupka K, Bender F, Gatterdam K, Putschli B, Fussholler D, Hilbig D, Kirchhoff A, Hunkler C, Wolter S, Grunewald A, Wallerath C, Schuberth-Wagner C, Ludwig J, Paeschke K, Bartok E, Hagelueken G, Hartmann G, Zillinger T, Geyer M, Schlee M Nucleic Acids Res. 2023 Nov 27;51(21):11893-11910. doi: 10.1093/nar/gkad835. PMID:37831086 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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