7BAI

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

Summary for 7BAI

• Entry DOI: 10.2210/pdb7bai/pdb
• Descriptor: Antiviral innate immune response receptor RIG-I, RNA (5'-R(*(GDP)P*AP*CP*GP*CP*UP*AP*GP*CP*GP*UP*C)-3'), ZINC ION (3 entities in total)
• Functional Keywords: rna recognition, innate immunity, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 56479.76

Authors

Anand, K.,Hagelueken, G.,Fusshoeller, D.,Geyer, M. (deposition date: 2020-12-15, release date: 2022-01-12, Last modification date: 2025-04-30)

Primary citation

de Regt, A.K.,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.
A conserved isoleucine in the binding pocket of RIG-I controls immune tolerance to mitochondrial RNA.
Nucleic Acids Res., 51:11893-11910, 2023

PubMed Abstract: 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.

PubMed: 37831086
DOI: 10.1093/nar/gkad835

Experimental method

X-RAY DIFFRACTION (3.4 Å)