ERN1

Serine/threonine-protein kinase/endoribonuclease IRE1 is an is_associated_with::enzyme that in humans is encoded by the ERN1 is_associated_with::gene.

Function
The protein encoded by this is_associated_with::gene is the ER to nucleus signalling 1 protein, a human is_associated_with::homologue of the yeast Ire1 gene product. This protein possesses intrinsic is_associated_with::kinase activity and an endoribonuclease activity and it is important in altering gene expression as a response to endoplasmic reticulum-based stress signals (mainly the is_associated_with::unfolded protein response). Two alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Signaling
IRE1a possesses two functional enzymatic domains, an is_associated_with::endonuclease and a trans-autophosphorylation kinase domain. Upon activation, IRE1a oligomerizes and carries out an unconventional RNA splicing activity, removing an is_associated_with::intron from the X-box binding protein 1 (is_associated_with::XBP1) mRNA, and allowing it to become translated into a functional is_associated_with::transcription factor, XBP1s. XBP1s upregulates ER chaperones and endoplasmic reticulum associated degradation (is_associated_with::ERAD) genes that facilitate recovery from is_associated_with::ER stress.

Interactions
ERN1 has been shown to interact with is_associated_with::Heat shock protein 90kDa alpha (cytosolic), member A1.

Inhibitors
Two types of inhibitors exist targeting either the catalytic core of the RNase domain or the ATP-binding pocket of the kinase domain.

RNase domain inhibitors
Salicylaldehydes (3-methoxy-6-bromosalicylaldehyde, 4μ8C, MKC-3946, STF-083010, toyocamycin.

ATP-binding pocket
is_associated_with::Sunitinib and APY29 inhibit the ATP-binding pocket but allosterically activate the IRE1α RNase domain.

Compound 3 prevents kinase activity, oligomerization and RNase activity.