Structure of Human RNase L Reveals the Basis for Regulated RNA Decay in the IFN Response

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Science  14 Mar 2014:
Vol. 343, Issue 6176, pp. 1244-1248
DOI: 10.1126/science.1249845

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Crossed Homodimer

Our cells respond to infection by releasing interferons, which protect neighboring cells, in part through the cleavage of intracellular RNA by a protein kinase family receptor, RNase L. RNase L is activated by 2′,5″-linked oligoadenylates (the second messenger 2-5 A), sensors of pathogen- and damage-associated RNA. Han et al. (p. 1244, published online 27 February) report crystal structures of human RNase L in complexes with 2-5 A, nucleotides, and an 18-nucleotide oligomer RNA target.


One of the hallmark mechanisms activated by type I interferons (IFNs) in human tissues involves cleavage of intracellular RNA by the kinase homology endoribonuclease RNase L. We report 2.8 and 2.1 angstrom crystal structures of human RNase L in complexes with synthetic and natural ligands and a fragment of an RNA substrate. RNase L forms a crossed homodimer stabilized by ankyrin (ANK) and kinase homology (KH) domains, which positions two kinase extension nuclease (KEN) domains for asymmetric RNA recognition. One KEN protomer recognizes an identity nucleotide (U), whereas the other protomer cleaves RNA between nucleotides +1 and +2. The coordinated action of the ANK, KH, and KEN domains thereby provides regulated, sequence-specific cleavage of viral and host RNA targets by RNase L.

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