A Noncatalytic Domain of Glycogen Synthase Kinase-3 (GSK-3) Is Essential for Activity
| Autor: | Christopher J. Phiel, Jessica L. Buescher |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Proline
tau Proteins macromolecular substances Kidney Transfection Biochemistry Glycogen Synthase Kinase 3 Axin Protein Isomerism GSK-3 Humans Phosphorylation Glycogen synthase Molecular Biology GSK3B Cells Cultured Glycogen Synthase Kinase 3 beta biology Kinase Wnt signaling pathway Cell Biology Enzyme structure Protein Structure Tertiary Enzyme Activation Repressor Proteins Wnt Proteins Protein Structure and Folding Mutagenesis Site-Directed biology.protein Tyrosine Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 285:7957-7963 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m109.091603 |
| Popis: | Glycogen synthase kinase-3 (GSK-3) isoforms, GSK-3alpha and GSK-3beta, 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-3alpha and GSK-3beta 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-3alpha/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. |
| Databáze: | OpenAIRE |
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