PDBsum entry 4g8l

Hydrolase

PDB id: 4g8l

Contents

Protein chain

307 a.a.

Ligands

25A ×4

References listed in PDB file

Key reference

• Title: Innate immune messenger 2-5a tethers human rnase l into active high-Order complexes.
• Authors: Y.Han, G.Whitney, J.Donovan, A.Korennykh.
• Ref.: Cell Rep, 2012, 2, 902-913. [DOI no: 10.1016/j.celrep.2012.09.004]
• PubMed id: 23084743

Abstract

2',5'-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 Å and 2.8 Å 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 Å 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.