6GPG

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

Summary for 6GPG

• Entry DOI: 10.2210/pdb6gpg/pdb
• Descriptor: RNA (5'-R(*CP*GP*AP*CP*GP*CP*UP*AP*GP*CP*GP*UP*CP*G)-3'), Probable ATP-dependent RNA helicase DDX58, ZINC ION, ... (4 entities in total)
• Functional Keywords: innate immune system, rig-i, singleton-merten syndrome, rna-dependent atpase, rna binding protein, antiviral protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 90941.53

Authors

Laessig, C.,Lammens, K.,Hopfner, K.-P. (deposition date: 2018-06-05, release date: 2018-08-08, Last modification date: 2024-05-15)

Primary citation

Lassig, C.,Lammens, K.,Gorenflos Lopez, J.L.,Michalski, S.,Fettscher, O.,Hopfner, K.P.
Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants.
Elife, 7:-, 2018

PubMed Abstract: The innate immune sensor retinoic acid-inducible gene I (RIG-I) detects cytosolic viral RNA and requires a conformational change caused by both ATP and RNA binding to induce an active signaling state and to trigger an immune response. Previously, we showed that ATP hydrolysis removes RIG-I from lower-affinity self-RNAs (Lässig et al., 2015), revealing how ATP turnover helps RIG-I 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, which is localized in the ATP-binding P-loop, can signal independently of ATP but is still dependent on RNA. The structure of RIG-I C268F in complex with double-stranded RNA reveals that C268F helps induce a structural conformation in RIG-I that is similar to that induced by ATP. Our results uncover an unexpected mechanism to explain how a mutation in a P-loop ATPase can induce a gain-of-function ATP state in the absence of ATP.

PubMed: 30047865
DOI: 10.7554/eLife.38958

Experimental method

X-RAY DIFFRACTION (2.894 Å)