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J Mol Neurosci. 2001 Oct;17(2):199-204.

gamma-Secretase inhibitors as molecular probes of presenilin function.

Author information

1
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. mwolfe@rics.bwh.harvard.edu

Abstract

Mutations in the presenilins cause Alzheimer's disease (AD) and alter gamma-secretase activity to increase the production of the 42-residue amyloid-beta peptide (Abeta) found disproportionally in the cerebral plaques that characterize the disease. The serpentine presenilins are required for transmembrane cleavage of both the amyloid-beta precursor protein (APP) and the Notch receptor by y-secretase, and presenilins are biochemically associated with the protease. Inhibitors of gamma-secretase have provided critical clues to the function of presenilins. Pharmacological profiling suggested that gamma-secretase is an aspartyl protease, leading to the identification of two conserved aspartates important to presenilin's role in proteolysis. Conversion of transition-state analogue inhibitors of gamma-secretase to affinity reagents resulted in specific tagging of the heterodimeric form of presenilins, strongly suggesting that the active site of gamma-secretase lies at the interface of the presenilin heterodimer. Heterodimeric presenilin appears to be the catalytic portion of a multi-protein gamma-secretase complex.

PMID:
11816793
DOI:
10.1385/JMN:17:2:199
[Indexed for MEDLINE]

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