Dec 24, 2015

Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis

The Journal of Cell Biology
Allen C ChenDennis J Selkoe

Abstract

Many single-transmembrane proteins are sequentially cleaved by ectodomain-shedding α-secretases and the γ-secretase complex, a process called regulated intramembrane proteolysis (RIP). These cleavages are thought to be spatially and temporally separate. In contrast, we provide evidence for a hitherto unrecognized multiprotease complex containing both α- and γ-secretase. ADAM10 (A10), the principal neuronal α-secretase, interacted and cofractionated with γ-secretase endogenously in cells and mouse brain. A10 immunoprecipitation yielded γ-secretase proteolytic activity and vice versa. In agreement, superresolution microscopy showed that portions of A10 and γ-secretase colocalize. Moreover, multiple γ-secretase inhibitors significantly increased α-secretase processing (r = -0.86) and decreased β-secretase processing of β-amyloid precursor protein. Select members of the tetraspanin web were important both in the association between A10 and γ-secretase and the γ → α feedback mechanism. Portions of endogenous BACE1 coimmunoprecipitated with γ-secretase but not A10, suggesting that β- and α-secretases can form distinct complexes with γ-secretase. Thus, cells possess large multiprotease complexes capable of sequentially and efficiently...Continue Reading

  • References53
  • Citations12

Mentioned in this Paper

Cricetulus
Gamma-Secretase Mediated ErbB4 Signaling Pathway
Protein Digestion
Integral Membrane Proteins
Complex (molecular entity)
Neurons
Amyloid Beta Precursor Protein Measurement
Brain
Chinese Hamster Ovary Cell
ADAM10

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