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• W2078665424 abstract "Glycogen synthase kinase-3 (GSK-3) isoforms, GSK-3α and GSK-3β, 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-3α and GSK-3β 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-3α/β Tyr279/216 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 Tyr279/216 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. Glycogen synthase kinase-3 (GSK-3) isoforms, GSK-3α and GSK-3β, 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-3α and GSK-3β 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-3α/β Tyr279/216 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 Tyr279/216 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." @default.
• W2078665424 created "2016-06-24" @default.
• W2078665424 creator A5030694429 @default.
• W2078665424 creator A5088244787 @default.
• W2078665424 date "2010-03-01" @default.
• W2078665424 modified "2023-09-30" @default.
• W2078665424 title "A Noncatalytic Domain of Glycogen Synthase Kinase-3 (GSK-3) Is Essential for Activity" @default.
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• W2078665424 doi "https://doi.org/10.1074/jbc.m109.091603" @default.
• W2078665424 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2832946" @default.
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