Nicastrin binds to membrane-tethered Notch

Fusheng Chen, Gang Yu, Shigeki Arawaka, Masaki Nishimura, Toshitaka Kawarai, Haung Yu, Anurag Tandon, Agnes Supala, You Qiang Song, Ekaterina Rogaeva, Paul Milman, Christine Sato, Cong Yu, Christopher Janus, Julie Lee, Lixin Song, Lili Zhang, Paul E. Fraser, P. H. St George-Hyslop

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Abstract

The presenilins 1,2 and nicastrin 3, a type 1 transmembrane glycoprotein, form high molecular weight complexes that are involved in cleaving the β-amyloid precursor protein (βAPP) 3-7 and Notch 8-11 in their transmembrane domains. The former process (termed γ-secretase cleavage) generates amyloid β-peptide (Aβ), 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 βAPP and the substrates of γ-secretase (C99- and C83-βAPP fragments), and modulates the activity of γ-secretase. Although absence of the Caenorhabditis elegans nicastrin homologue (aph-2) is known to cause an embryonic-lethal glp-1 phenotype 3,12, 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 γ-secretase, they only weakly modulate the S3-site cleavage of Notch. Thus, nicastrin has a similar role in processing Notch and βAPP, but the 312-369 domain may have differential effects on these activities. In addition, we report that the Notch and βAPP pathways do not significantly compete with each other.

Original languageEnglish (US)
Pages (from-to)751-754
Number of pages4
JournalNature cell biology
Volume3
Issue number8
DOIs
StatePublished - Aug 21 2001

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Chen, F., Yu, G., Arawaka, S., Nishimura, M., Kawarai, T., Yu, H., Tandon, A., Supala, A., Song, Y. Q., Rogaeva, E., Milman, P., Sato, C., Yu, C., Janus, C., Lee, J., Song, L., Zhang, L., Fraser, P. E., & St George-Hyslop, P. H. (2001). Nicastrin binds to membrane-tethered Notch. Nature cell biology, 3(8), 751-754. https://doi.org/10.1038/35087069