@article{2567, keywords = {Molecular Sequence Data, Humans, Signal Transduction, Protein Binding, Protein Structure, Tertiary, Crystallography, X-Ray, Dimerization, Amino Acid Sequence, Sequence Alignment, Immunity, Innate, Protein Multimerization, Endoribonucleases, Ankyrins, Cross-Linking Reagents, Oxidation-Reduction}, author = {Yuchen Han and Gena Whitney and Jesse Donovan and Alexei Korennykh}, title = {Innate immune messenger 2-5A tethers human RNase L into active high-order complexes.}, abstract = {
2{\textquoteright},5{\textquoteright}-linked oligoadenylates (2-5As) serve as conserved messengers of pathogen presence in the mammalian innate immune system. 2-5As induce self-association and activation of RNase L, which cleaves cytosolic RNA and promotes the production of interferons (IFNs) and cytokines driven by the transcription factors IRF-3 and NF-κB. We report that human RNase L is activated by forming high-order complexes, reminiscent of the mode of activation of the phylogenetically related transmembrane kinase/RNase Ire1 in the unfolded protein response. We describe crystal structures determined at 2.4~{\r A} and 2.8~{\r A} resolution, which show that two molecules of 2-5A at a time tether RNase L monomers via the ankyrin-repeat (ANK) domain. Each ANK domain harbors two distinct sites for 2-5A recognition that reside 50~{\r A} apart. These data reveal a function for the ANK domain as a 2-5A-sensing homo-oligomerization device and describe a nonlinear, ultrasensitive regulation in the 2-5A/RNase L system poised for amplification of the IFN response.
}, year = {2012}, journal = {Cell Rep}, volume = {2}, pages = {902-13}, month = {2012 Oct 25}, issn = {2211-1247}, doi = {10.1016/j.celrep.2012.09.004}, language = {eng}, }