Presenilin‐dependent γ‐secretase processing of β‐amyloid precursor protein at a site corresponding to the S3 cleavage of Notch

EMBO Reports - Tập 2 Số 9 - Trang 835-841 - 2001
Magdalena Sastre1, Harald Steiner1, Klaus Fuchs2, Anja Capell1, Gerd Multhaup3, Margaret M. Condron4, David B. Teplow4, Christian Haass1
1Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians University, Schillerstrasse 44, 80336 Munich, Germany
2Boehringer Ingelheim Pharma KG, Chemical Research 55216 Ingelheim Germany
3Center for Molecular Biology Heidelberg Im Neuenheimer Feld 282 69120 Heidelberg Germany
4Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA

Tóm tắt

The presenilin (PS)‐dependent site 3 (S3) cleavage of Notch liberates its intracellular domain (NICD), which is required for Notch signaling. The similar γ‐secretase cleavage of the β‐amyloid precursor protein (βAPP) results in the secretion of amyloid β‐peptide (Aβ). However, little is known about the corresponding C‐terminal cleavage product (CTFγ). We have now identified CTFγ in brain tissue, in living cells, as well as in an in vitro system. Generation of CTFγ is facilitated by PSs, since a dominant‐negative mutation of PS as well as a PS gene knock out prevents its production. Moreover, γ‐secretase inhibitors, including one that is known to bind to PS, also block CTFγ generation. Sequence analysis revealed that CTFγ is produced by a novel γ‐secretase cut, which occurs at a site corresponding to the S3 cleavage of Notch.

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EMBO Reports

Tập 2 Số 9

835-841

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