Presenilin-1 is an Unprimed Glycogen Synthase Kinase-3beta Substrate.
From: Signal Transduction Laboratory, Biochemistry Department, National University of Ireland, Cork, Ireland.
FEBS letters
- Publish Date: Jul 2006
- ISSN: 0014-5793
- Volume: 580
- Issue: 17
- Pages: 4015-20
- Medium: Print
- Language: English
- Citation (JAMA): Twomey Ciara, McCarthy Justin V, et al. Presenilin-1 is an Unprimed Glycogen Synthase Kinase-3beta Substrate.. FEBS Lett. Jul 2006;580:4015-20
Abstract
Previously we described presenilin-1 (PS1) as a GSK-3beta substrate [Kirschenbaum, F., Hsu, S.C., Cordell, B. and McCarthy, J.V.(2001) Substitution of a glycogen synthase kinase-3beta phosphorylation site in presenilin 1 separates presenilin function from beta-catenin signalling. J. Biol. Chem. 276, 7366-7375; Kirschenbaum, F., Hsu, S.C., Cordell, B. and McCarthy, J.V.(2001) Glycogen synthase kinase-3beta regulates presenilin 1 C-terminal fragment levels. J. Biol. Chem. 276, 30701-30707], though it has not been determined whether PS1 is a primed or unprimed GSK-3beta substrate. A means of separating GSK-3beta activity toward primed and unprimed substrates was identified in the GSK-3beta-R96A phosphate binding pocket mutant [Frame, S., Cohen, P. and Biondi, R.M.(2001) A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol. Cell 7, 1321-1327], which is unable to phosphorylate primed but retains the ability to phosphorylate unprimed GSK-3beta substrates. By using wild type GSK-3beta, GSK-3beta-R96A, and a pharmacological modulator of GSK-3beta activity, we demonstrate that PS1 is an unprimed GSK-3beta substrate. These findings have important implications for regulation of PS1 function and the pathogenesis of Alzheimer’s disease.
Mesh Headings (Keywords): Alzheimer Disease, Amino Acid Sequence, Amino Acid Substitution, Animals, Binding Sites, Cell Line, Glycogen Synthase Kinase 3, Humans, Membrane Proteins, Molecular Sequence Data, Phosphorylation, Point Mutation, Presenilin-1, Protein Processing, Post-Translational, Substrate Specificity
Check for Full Text / PubMed Unique Identifier (PMID): 16814287
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