(Download) "Structure-Function Analysis of GSK-3 Isoforms" by Jessica L. Buescher " eBook PDF Kindle ePub Free
eBook details
- Title: Structure-Function Analysis of GSK-3 Isoforms
- Author : Jessica L. Buescher
- Release Date : January 18, 2013
- Genre: Medical,Books,Professional & Technical,
- Pages : * pages
- Size : 12296 KB
Description
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’s disease, diabetes, and mood disorders. Accumulating evidence suggests that GSK-3 isoforms exhibit distinct activities and increasingly challenges the conventional belief that GSK-3 isoforms are functionally redundant. Despite abundant GSK-3-related research, the basis for differential functions of GSK-3 isoforms remains unresolved. Logically, the divergent regions of GSK-3, the N- and C-termini, might be predicted to mediate the differential activities of GSK-3 isoforms at the post-translational level. Herein we test the hypothesis that the divergent N- and C-terminal regions and conserved key residues of GSK-3 isoforms are functionally significant. To test our hypothesis we performed a structure-function analysis of GSK-3α and GSK-3β in mammalian cells. Deletion constructs of the non-catalytic N- and C-terminal domains in both GSK-3 isoforms were created as well as constructs containing point mutations of key regulatory residues. We examined the effect of these deletions and point mutations on GSK-3 activity, protein interactions, tyrosine autophosphorylation, and subcellular localization. We found that the N-termini of both GSK-3 isoforms are dispensable for activity, protein interaction with Axin GID, and tyrosine autophosphorylation, but are required for the GSK-3α-specific interaction with RACK1 WD4-7 and proper localization. In turn, progressive C-terminal deletions resulted in a loss of activity, impaired ability to interact with protein binding partners, a gradual loss of autophosphorylation, and mislocalization. Taken together, these observations imply that deletion of the C-termini of GSK-3 isoforms compromises proper protein folding and suggest that the C-terminal regions make significant contributions to the structural integrity of GSK-3 enzymes. Furthermore, our data predict that the development of therapeutic modulators targeting the C-terminus may result in isoform-specific GSK-3 inhibition through destabilization of GSK-3 structure.
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