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Nucleic Acids Res. 2017 Feb 17;45(3):1442-1454. doi: 10.1093/nar/gkw816.

Selective RNA targeting and regulated signaling by RIG-I is controlled by coordination of RNA and ATP binding.

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Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA


RIG-I is an innate immune receptor that detects and responds to infection by deadly RNA viruses such as influenza, and Hepatitis C. In the cytoplasm, RIG-I is faced with a difficult challenge: it must sensitively detect viral RNA while ignoring the abundance of host RNA. It has been suggested that RIG-I has a ‘proof-reading’ mechanism for rejecting host RNA targets, and that disruptions of this selectivity filter give rise to autoimmune diseases. Here, we directly monitor RNA proof-reading by RIG-I and we show that it is controlled by a set of conserved amino acids that couple RNA and ATP binding to the protein (Motif III). Mutations of this motif directly modulate proof-reading by eliminating or enhancing selectivity for viral RNA, with major implications for autoimmune disease and cancer. More broadly, the results provide a physical explanation for the ATP-gated behavior of SF2 RNA helicases and receptor proteins.

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