RIG-I uses an ATPase-powered translocation-throttling mechanism for kinetic proofreading of RNAs and oligomerization

By S. Devarkar, Brandon D Schweibenz, Chen Wang, J. Marcotrigiano, Smita S. Patel. 2018

66 citations recorded by the source corpus.

Summary RIG-I has a remarkable ability to specifically select viral 5’ppp dsRNAs for activation from a pool of cytosolic self-RNAs. The ATPase activity of RIG-I plays a role in RNA discrimination and activation, but the underlying mechanism was unclear. Using transient state kinetics, we have elucidated the ATPase-driven ‘kinetic proofreading’ mechanism of RIG-I activation and RNA discrimination, akin to DNA polymerases, ribosomes, and T-cell receptors. Even in the autoinhibited state of RIG-I, the C-terminal domain kinetically discriminates against self-RNAs by fast off-rates. ATP-binding facilitates dsRNA engagement, but interestingly makes RIG-I promiscuous, explaining the constitutive signaling by Singleton-Merton syndrome-linked mutants that bind ATP without hydrolysis. ATP hydrolysis dissociates self-RNAs faster than 5’ppp dsRNA, but more importantly, drives RIG-I oligomerization through translocation, that we show is regulated by helicase motif-IVa. RIG-I translocates directionally from dsRNA-end into stem-region and 5’ppp-end “throttles” translocation to provide a mechanism for threading and building a signaling-active oligomeric complex.

Subfields: Cardiology and Cardiovascular Medicine, Immunology, Molecular Biology

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In Cardiology and Cardiovascular Medicine

1. Wenshuai Wang
2. Anna Marie Pyle

In Immunology

1. Wenshuai Wang
2. Anna Marie Pyle
3. T. Dickey
4. B. Song

In Molecular Biology

1. Wenshuai Wang
2. T. Dickey
3. B. Song
4. Anna Marie Pyle

Citations in the corpus

• The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands (2022, positive): “Indeed, direct studies of RIG-I binding to internal duplexes has shown that these complexes are very weak (4–5 orders of magnitude weaker than binding to the terminus of RNA duplexes (Devarkar et al., 2018; Rawling et al., 2015; Ren et al., 2019; Vela et al., 2012).”
• RNA binding activates RIG-I by releasing an autorepressed signaling domain (2019, background): “Evolution of the pincer domain in RIG-I–like proteins resulted in a conformational alteration that prevents translocation via the mechanism established for SF2 proteins such as NS3 (43), perhaps explaining slow rates of apparent RIG-I motion on RNA (23) and suggesting a nonprocessive mechanism much ”