Format

Send to

Choose Destination
J Biol Chem. 2010 Mar 12;285(11):7957-63. doi: 10.1074/jbc.M109.091603. Epub 2010 Jan 15.

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

Author information

1
Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.

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.

PMID:
20080974
PMCID:
PMC2832946
DOI:
10.1074/jbc.M109.091603
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center