A Noncatalytic Domain of Glycogen Synthase Kinase-3 (GSK-3) Is Essential for Activity

作者：Buescher Jessica L; Phiel Christopher J^*

来源：Journal of Biological Chemistry, 2010, 285(11): 7957-7963.

DOI：10.1074/jbc.M109.091603

Glycogen synthase kinase-3 (GSK-3) isoforms, GSK-3 alpha and GSK-3 beta, are serine/threonine kinases involved in numerous cellular processes and diverse diseases, including Alzheimer disease, cancer, and diabetes. GSK-3 isoforms function redundantly in some settings, while, in others, they exhibit distinct activities. Despite intensive investigation into the physiological roles of GSK-3 isoforms, the basis for their differential activities remains unresolved. A more comprehensive understanding of the mechanistic basis for GSK-3 isoform-specific functions could lead to the development of isoform-specific inhibitors. Here, we describe a structure-function analysis of GSK-3 alpha and GSK-3 beta in mammalian cells. We deleted the noncatalytic N and C termini in both GSK-3 isoforms and generated point mutations of key regulatory residues. We examined the effect of these mutations on GSK-3 activity toward Tau, activity in Wnt signaling, interaction with Axin, and GSK-3 alpha/beta Tyr(279/216) phosphorylation. We found that the N termini of both GSK-3 isoforms were dispensable, whereas progressive C-terminal deletions resulted in protein misfolding exhibited by deficient activity, impaired ability to interact with Axin, and a loss of Tyr(279/216) phosphorylation. Our data predict that small molecules targeting the divergent C terminus may lead to isoform-specific GSK-3 inhibition through destabilization of the GSK-3 structure.

• 出版日期2010-3-12