Nicastrin binds to membrane-tethered Notch

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 - 1 1 in their transmembrane domains. The former process (termed γ-secretase cleavage) generates amyloid p-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-pAPP 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 , 1 2 , 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.