A noncatalytic domain of glycogen synthase kinase-3 (GSK-3) is essential for activity.

Abstract

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.

• Authors: Jessica L Buescher, Christopher J Phiel
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 11 Pg. 7957-63 (Mar 12 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20080974 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Axin Protein
• MAPT protein, human
• Repressor Proteins
• Wnt Proteins
• tau Proteins
• Tyrosine
• Proline
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Glycogen Synthase Kinase 3
• glycogen synthase kinase 3 alpha

Topics

• Axin Protein
• Cells, Cultured
• Enzyme Activation (physiology)
• Glycogen Synthase Kinase 3 (chemistry, genetics, metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Isomerism
• Kidney (cytology)
• Mutagenesis, Site-Directed
• Phosphorylation
• Proline (metabolism)
• Protein Structure, Tertiary
• Repressor Proteins (metabolism)
• Signal Transduction (physiology)
• Transfection
• Tyrosine (metabolism)
• Wnt Proteins (metabolism)
• tau Proteins (metabolism)