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Nucleic Acids Res. 2014 Oct;42(18):11601-11. doi: 10.1093/nar/gku817. Epub 2014 Sep 12.

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

Author information

1
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
2
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA Department of Chemistry, Yale University, New Haven, CT 06520, USA.
3
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA Department of Chemistry, Yale University, New Haven, CT 06520, USA anna.pyle@yale.edu.

Abstract

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.

PMID:
25217590
PMCID:
PMC4191399
DOI:
10.1093/nar/gku817
[Indexed for MEDLINE]
Free PMC Article

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