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Biophys J. 2015 Mar 10;108(5):1229-37. doi: 10.1016/j.bpj.2014.12.045.

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

Author information

1
Metabolic Biochemistry, Ludwig-Maximilians-University, München, Germany.
2
Metabolic Biochemistry, Ludwig-Maximilians-University, München, Germany; DZNE-German Center for Neurodegenerative Diseases, Munich, Germany.
3
Metabolic Biochemistry, Ludwig-Maximilians-University, München, Germany; DZNE-German Center for Neurodegenerative Diseases, Munich, Germany. Electronic address: harald.steiner@med.uni-muenchen.de.

Abstract

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 β-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.

PMID:
25762334
PMCID:
PMC4375682
DOI:
10.1016/j.bpj.2014.12.045
[Indexed for MEDLINE]
Free PMC Article

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