Purification, Pharmacological Modulation, and Biochemical Characterization of Interactors of Endogenous Human γ-Secretase†
作者： Edith Winkler , Scott Hobson , Akio Fukumori , Birgit Dümpelfeld , Thomas Luebbers
DOI: 10.1021/BI801204G
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摘要: γ-Secretase is a unique intramembrane-cleaving protease complex, which cleaves the Alzheimer′s disease-associated β-amyloid precursor protein (APP) and number of other type I membrane proteins. Human γ-secretase consists catalytic subunit presenilin (PS) (PS1 or PS2), substrate receptor nicastrin, APH-1 (APH-1a APH-1b), PEN-2. To facilitate in-depth biochemical analysis γ-secretase, we developed fast convenient multistep purification procedure for endogenous enzyme. The enzyme was purified from HEK293 cells in an active form had molecular mass ∼500 kDa. Purified capable producing major amyloid-β peptide (Aβ) species, such as Aβ40 Aβ42, recombinant APP physiological ratios. Aβ generation could be modulated by pharmacological modulators. Moreover, Aβ42/Aβ40 ratio strongly increased PS1 L166P, aggressive familial Alzheimer’s disease mutant. Tandem spectrometry revealed the...
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