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

Gang Yu, Masaki Nishimura, Shigeki Arawaka, Diane Levitan, Lili Zhang, Anurag Tandon, You Qiang Song, Ekaterina Rogaeva, Fusheng Chen, Toshitaka Kawarai, Agnes Supala, Lyne Levesque, Haung Yu, Dun Sheng Yang, Erin Holmes, Paul Milman, Yan Liang, Dong Mel Zhang, Dong Hong Xu, Christine SatoEvgeny Rogaev, Marsha Smith, Christopher Janus, Yanni Zhang, Ruedl Aebersold, Lindsay Farrer, Sandro Sorbl, Amalia Bruni, Paul Fraser, Peter St George-Hyslop

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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 β-amyloid precursor protein (βAPP), and modulates the production of the amyloid β-peptide (Aβ) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase Aβ42 and Aβ40 peptide secretion. Deletions in this domain inhibit Aβ 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 βAPP.

Original languageEnglish (US)
Pages (from-to)48-54
Number of pages7
JournalNature
Volume407
Issue number6800
DOIs
StatePublished - Sep 1 2000

ASJC Scopus subject areas

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    Yu, G., Nishimura, M., Arawaka, S., Levitan, D., Zhang, L., Tandon, A., Song, Y. Q., Rogaeva, E., Chen, F., Kawarai, T., Supala, A., Levesque, L., Yu, H., Yang, D. S., Holmes, E., Milman, P., Liang, Y., Zhang, D. M., Xu, D. H., ... George-Hyslop, P. S. (2000). Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature, 407(6800), 48-54. https://doi.org/10.1038/35024009