title: Nicastrin binds to membrane-tethered Notch.
abstract: The presenilins and nicastrin, a type 1 transmembrane glycoprotein, form high molecular weight complexes that are involved in cleaving the beta-amyloid precursor protein (betaAPP) and Notch in their transmembrane domains. The former process (termed gamma-secretase cleavage) generates amyloid beta-peptide (Abeta), which is involved in the pathogenesis of Alzheimer's disease. The latter process (termed S3-site cleavage) generates Notch intracellular domain (NICD), which is involved in intercellular signalling. Nicastrin binds both full-length betaAPP and the substrates of gamma-secretase (C99- and C83-betaAPP fragments), and modulates the activity of gamma-secretase. Although absence of the Caenorhabditis elegans nicastrin homologue (aph-2) is known to cause an embryonic-lethal glp-1 phenotype, the role of nicastrin in this process has not been explored. Here we report that nicastrin binds to membrane-tethered forms of Notch (substrates for S3-site cleavage of Notch), and that, although mutations in the conserved 312-369 domain of nicastrin strongly modulate gamma-secretase, they only weakly modulate the S3-site cleavage of Notch. Thus, nicastrin has a similar role in processing Notch and betaAPP, but the 312-369 domain may have differential effects on these activities. In addition, we report that the Notch and betaAPP pathways do not significantly compete with each other.
authors.affiliation: Centre for Research in Neurodegenerative Diseases; Departments of Medicine and Medical Biophysics, University of Toronto, Tanz Neuroscience Building, 6 Queen's Park Crescent West, Toronto, Ontario M5S 3H2, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Chen
authors.forename: G
authors.initials: G
authors.lastname: Yu
authors.forename: S
authors.initials: S
authors.lastname: Arawaka
authors.forename: M
authors.initials: M
authors.lastname: Nishimura
authors.forename: T
authors.initials: T
authors.lastname: Kawarai
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: A
authors.initials: A
authors.lastname: Tandon
authors.forename: A
authors.initials: A
authors.lastname: Supala
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Song
authors.forename: E
authors.initials: E
authors.lastname: Rogaeva
authors.forename: P
authors.initials: P
authors.lastname: Milman
authors.forename: C
authors.initials: C
authors.lastname: Sato
authors.forename: C
authors.initials: C
authors.lastname: Yu
authors.forename: C
authors.initials: C
authors.lastname: Janus
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: L
authors.initials: L
authors.lastname: Song
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: P E
authors.initials: PE
authors.lastname: Fraser
authors.forename: P H
authors.initials: PH
authors.lastname: St George-Hyslop
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases; D001665:Binding Sites / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051880:Receptors, Notch; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D051880:Receptors, Notch; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human