A kinase-dead Ire1 (right) is resuscitated by 1NM-PP1.

Papa/AAAS

A new output mode for a kinase is reported by Feroz Papa, Peter Walter, and colleagues (HHMI and University of California, San Francisco [UCSF], CA). They find that, for Ire1 kinase, the key to activation is not phosphotransfer but rather ligand binding in the kinase's nucleotide-binding site. Occupancy of that site restores function to a kinase-dead mutant of Ire1.

The new findings just add to the uniqueness of the Ire1 pathway, which responds to unfolded proteins. “This pathway is really a sort of duckbilled platypus,” says Papa. “There have been so many surprises.”

The response starts when unfolded proteins recruit chaperones away from Ire1; this is thought to expose a patch on Ire1 that mediates oligomerization. Transphosphorylation by Ire1 oligomers then somehow activates the RNase activity of Ire1, which excises an inhibitory intron from the HAC1...

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