Presenilin-1 is an unprimed glycogen synthase kinase-3beta substrate.
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.
Twomey
Ciara
C
Signal Transduction Laboratory, Biochemistry Department, National University of Ireland, Cork, Ireland.
McCarthy
Justin V
JV
D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017354:Point Mutation; D053764:Presenilin-1; D011499:Protein Processing, Post-Translational / Q000235:genetics; D013379:Substrate Specificity
D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3