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

Content Provider	PubMed Central
Author	Buescher, Jessica L. Phiel, Christopher J.
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.
Related Links	http://dx.doi.org/10.1074/jbc.m109.091603
Ending Page	7963
Page Count	7
Starting Page	7957
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	11
Volume Number	285
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2010-03-12
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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