The RIG-I ATPase core has evolved a functional requirement for allosteric stabilization by the Pincer domain

By David C. Rawling, Andrew S. Kohlway, D. Luo, S. Ding, Anna Marie Pyle. 2014

30 citations recorded by the source corpus.

Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor expressed in metazoan cells that is responsible for eliciting the production of type I interferons and pro-inflammatory cytokines upon detection of intracellular, non-self RNA. Structural studies of RIG-I have identified a novel Pincer domain composed of two alpha helices that physically tethers the C-terminal domain to the SF2 helicase core. We find that the Pincer plays an important role in mediating the enzymatic and signaling activities of RIG-I. We identify a series of mutations that additively decouple the Pincer motif from the ATPase core and show that this decoupling results in impaired signaling. Through enzymological and biophysical analysis, we further show that the Pincer domain controls coupled enzymatic activity of the protein through allosteric control of the ATPase core. Further, we show that select regions of the HEL1 domain have evolved to potentiate interactions with the Pincer domain, resulting in an adapted ATPase cleft that is now responsive to adjacent domains that selectively bind viral RNA.

Subfields: Immunology, Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

In Molecular Biology

Citations in the corpus

The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands (2022, positive): “action of Hel1, Hel2, and the C-terminal domain (CTD) (Rawling et al., 2014), and in this set of structures we observe that it forms a direct contact with the RNA at position C8 (via 750, Figure 1G and S8).”
Kinetic discrimination of self/non-self RNA by the ATPase activity of RIG-I and MDA5 (2015, unknown): “The CARD-hel domain is also auto-repressed showing that the CTD is not required to maintain this state [30, 57] (Fig.”
Establishing the role of ATP for the function of the RIG-I innate immune sensor (2015, background): “It has been demonstrated that duplex RNAs containing a 5′ hydroxyl can bind RIG-I and stimulate robust ATP hydrolysis (Kohlway et al., 2013; Rawling et al., 2015), yet these RNAs do not induce immune signaling by RIGI, even at saturating concentrations (Schlee et al., 2009; Baum et al., 2010;…”
A minimal RNA ligand for potent RIG-I activation in living mice (2017, result): “Together, these findings confirm previous work demonstrating the potency of SLRs in cell culture (10, 37, 38) and benchmark SLR potency relative to other putative RIG-I ligands.”
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 ”