Protein kinases function not only as catalysts but also as scaffolds and docking targets. Papa et al. now show how an unanticipated conformation-dependent activation of the kinase Ire1 activates the "unfolded protein response" from within the endoplasmic reticulum. This response stimulates the production of protein chaperones and other factors to enhance the cell's ability to cope with the buildup of misfolded proteins within the secretory pathway. The conformational change can be mimicked by a bulky adenosine 5′-triphosphate (ATP) analog when the ATP binding site is modified. The activation of the RNA splicing activity promoted by Ire1 is surprisingly independent of phosphorylation.
F. R. Papa, C. Zhang, K. Shokat, P. Walter, Bypassing a kinase activity with an ATP-competitive drug. Science 302, 1533-1537 (2003). [Abstract] [Full Text]
