The presenilins1,2 and nicastrin3, a type 1 transmembrane glycoprotein, form high molecular weight complexes that are involved in cleaving the β-amyloid precursor protein (βAPP)3,4,5,6,7 and Notch8,9,10,11 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 phenotype3,12, 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.
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We thank Dr F. Checler for the gift of antibodies FAC3340, FAC3542 and FAC18.This work was supported by grants from the Canadian Institutes of Health Research, Alzheimer Association of Ontario, Howard Hughes Medical Research Foundation, Scottish Rite Charitable Foundation, Helen B. Hunter Fellowship (G.Y.), Peterborough Burgess Fellowship (E.A.R.); University of Toronto Department of Medicine Postgraduate Fellowship (M.N.) and Japan Society for the Promotion of Science (T.K.).
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