Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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Intramembrane proteolysis of β-amyloid precursor protein by γ-secretase is an unusually slow process

Biophys J. 2015 Mar 10;108(5):1229-37.

Authors/Editors: Frits Kamp
Edith Winkler
Johannes Trambauer
Amelie Ebke
Regina Fluhrer
Harald Steiner
Publication Date: 2015
Type of Publication: Journal Article

Intramembrane proteolysis has emerged as a key mechanism required for membrane proteostasis and cellular signaling. One of the intramembrane-cleaving proteases (I-CLiPs), γ-secretase, is also intimately implicated in Alzheimer’s disease, a major neurodegenerative disease and leading cause of dementia. High-resolution crystal structural analyses have revealed that I-CLiPs harbor their active sites buried deeply in the membrane bilayer. Surprisingly, however, the key kinetic constants of these proteases, turnover number kcat and catalytic efficiency kcat/KM, are largely unknown. By investigating the kinetics of intramembrane cleavage of the Alzheimer’s disease-associated b-amyloid precursor protein in vitro and in human embryonic kidney cells, we show that γ-secretase is a very slow protease with a kcat value similar to those determined recently for rhomboid-type I-CLiPs. Our results indicate that low turnover numbers may be a general feature of I-CLiPs.

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