title: Cyclin-dependent kinase-5/p35 phosphorylates Presenilin 1 to regulate carboxy-terminal fragment stability.
abstract: Mutations in the Presenilin 1 gene are the cause of the majority of autosomal dominant familial forms of Alzheimer's disease. Presenilin 1 (PS1) is produced as a holoprotein but is then rapidly processed to amino- (N-PS1) and carboxy-terminal (C-PS1) fragments that are incorporated into stable high molecular mass complexes. The mechanisms that control PS1 cleavage and stability are not properly understood but sequences within C-PS1 have been shown to regulate both of these properties. Here we demonstrate that cyclin dependent kinase-5/p35 (cdk5/p35) phosphorylates PS1 on threonine(354) within C-PS1 both in vitro and in vivo. Threonine(354) phosphorylation functions to selectively stabilize C-PS1. Our results demonstrate that cdk5/p35 is a regulator of PS1 metabolism.
authors.affiliation: Department of Neuroscience, The Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, United Kingdom.
authors.forename: Kwok-Fai
authors.initials: KF
authors.lastname: Lau
authors.forename: David R
authors.initials: DR
authors.lastname: Howlett
authors.forename: Sashi
authors.initials: S
authors.lastname: Kesavapany
authors.forename: Claire L
authors.initials: CL
authors.lastname: Standen
authors.forename: Colin
authors.initials: C
authors.lastname: Dingwall
authors.forename: Declan M
authors.initials: DM
authors.lastname: McLoughlin
authors.forename: Christopher C J
authors.initials: CC
authors.lastname: Miller
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000503:physiopathology; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000201:enzymology*; D002540:Cerebral Cortex / Q000201:enzymology* / Q000503:physiopathology; D006224:Cricetinae; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology*; D010446:Peptide Fragments / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D053764:Presenilin-1; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D014162:Transfection
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases; D010749:Phosphoprotein Phosphatases