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 bet a -amyloid precursor protein (beta APP)(3-7) and Notch(8-11) in their trans membrane domains. The former process (termed gamma -secretase cleavage) gen erates amyloid beta -peptide (A beta), which is involved in the pathogenesi s of Alzheimer's disease. The latter process (termed S3-site cleavage) gene rates Notch intracellular domain (NICD), which is involved in intercellular signalling. Nicastrin binds both full-length beta APP and the substrates o f gamma -secretase (C99- and C83-beta APP fragments), and modulates the act ivity of gamma -secretase. Although absence of the Caenorhabditis elegans n icastrin homologue (aph-2) is known to cause an embryonic-lethal glp-1 phen otype(3,12), the role of nicastrin in this process has not been explored. H ere we report that nicastrin binds to membrane-tethered forms of Notch (sub strates for S3-site cleavage of Notch), and that, although mutations in the conserved 312-369 domain of nicastrin strongly modulate gamma -secretase, they only weakly modulate the S3-site cleavage of Notch. Thus, nicastrin ha s a similar role in processing Notch and beta APP, but the 312-369 domain m ay have differential effects on these activities. In addition, we report th at the Notch and beta APP pathways do not significantly compete with each o ther.