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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Amyloid Precursor Protein Secretases
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Aspartic Acid Endopeptidases
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Caenorhabditis elegans
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Caenorhabditis elegans Proteins*
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DNA, Complementary
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Endopeptidases / metabolism
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Humans
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Membrane Glycoproteins / physiology*
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Membrane Proteins / metabolism*
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Molecular Sequence Data
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Presenilin-1
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Presenilin-2
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Receptors, Notch
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Sequence Homology, Amino Acid
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Signal Transduction*
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Transfection
Substances
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Amyloid beta-Protein Precursor
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Caenorhabditis elegans Proteins
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DNA, Complementary
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Glp-1 protein, C elegans
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Membrane Glycoproteins
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Membrane Proteins
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PSEN1 protein, human
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PSEN2 protein, human
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Presenilin-1
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Presenilin-2
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Receptors, Notch
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nicastrin protein
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE1 protein, human