Presenilin dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch

The presenilin (PS)-dependent site 3 (S3) cleavage of Notch liberates its i ntracellular domain (NICD), which is required for Notch signaling. The simi lar gamma -secretase cleavage of the beta -amyloid precursor protein (beta APP) results in the secretion of amyloid beta -peptide (AP). However, littl e is known about the corresponding C-terminal cleavage product (CTF gamma). We have now identified CTF gamma in brain tissue, in living cells, as well as in an in vitro system. Generation of CTF gamma is facilitated by PSs, s ince a dominant-negative mutation of PS as well as a PS gene knock out prev ents its production. Moreover, gamma -secretase inhibitors, including one t hat is known to bind to PS, also block CTF gamma generation. Sequence analy sis revealed that CTF gamma is produced by a novel gamma -secretase cut, wh ich occurs at a site corresponding to the S3 cleavage of Notch.