Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing

Nature. 2000 Sep 7;407(6800):48-54. doi: 10.1038/35024009.

Abstract

Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of beta-amyloid precursor protein (betaAPP), and modulates the production of the amyloid beta-peptide (A beta) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase A beta42 and A beta40 peptide secretion. Deletions in this domain inhibit A beta production. Nicastrin and presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and betaAPP.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins*
  • DNA, Complementary
  • Endopeptidases / metabolism
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Glycoproteins / physiology*
  • Membrane Proteins / metabolism*
  • Molecular Sequence Data
  • Presenilin-1
  • Presenilin-2
  • Receptors, Notch
  • Sequence Homology, Amino Acid
  • Signal Transduction*
  • Transfection

Substances

  • Amyloid beta-Protein Precursor
  • Caenorhabditis elegans Proteins
  • DNA, Complementary
  • Glp-1 protein, C elegans
  • Membrane Glycoproteins
  • Membrane Proteins
  • PSEN1 protein, human
  • PSEN2 protein, human
  • Presenilin-1
  • Presenilin-2
  • Receptors, Notch
  • nicastrin protein
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human

Associated data

  • GENBANK/AF240468