InterPro domain: IPR038357

The proteins listed below share a common architecture with a protein kinase homology domain (see PDOC00100 ) followed by an ~135-residue globular kinase-extension nuclease (KEN) domain made of eight helices [ 1 ]:

• Mammalian 2-5A-dependent RNase or RNase L (EC 3.1.26.-), an interferon-induced enzyme implicated in both the molecular mechanisms of interferon action and the fundamental control of RNA stability. 2-5A-dependent RNase is a unique enzyme in that it requires 2-5A, unusual oligoadenylates with 2',5'-phosphodiester linkages. RNase L is catalytically active only after binding to an unusual activator molecule containing a 5'-phosphorylated 2', 5'-linked oligoadenylate (2-5A), in the N-terminal half. RNase L consists of three domains, namely the N-terminal ankyrin repeat domain (see PDOC50088 ), the protein kinase homology domain, and the C-terminal KEN domain [ 2 , 3 , 4 ].
• Eukaryotic Ire1/Ern1, an ancient transmembrane sensor of endoplasmic reticulum (ER) stress with dual protein kinase and ribonuclease activities. In response to ER stress Ire1/Ern1 catalyzes the splicing of target mRNAs in a spliceosome-independent manner. Ire1/Ern1 is a type 1 transmembrane receptor consisting of an N-terminal ER luminal domain, a transmembrane segment and a cytoplasmic region. The cytoplasmic region encompasses a protein kinase domain followed by a C-terminal KEN domain [ 5 , 5 ].

The dimerisation of the kinase domain activates the ribonuclease function of the KEN domain [ 6 ].

1. Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing. Cell 132, 89-100
2. Expression cloning of 2-5A-dependent RNAase: a uniquely regulated mediator of interferon action. Cell 72, 753-65
3. Structural basis for recognition of 2',5'-linked oligoadenylates by human ribonuclease L. EMBO J. 23, 3929-38
4. A viral RNA competitively inhibits the antiviral endoribonuclease domain of RNase L. RNA 14, 1026-36
5. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 12, 1812-24