Oct 11, 2013

Substrate ectodomain is critical for substrate preference and inhibition of γ-secretase

Nature Communications
Satoru FunamotoYasuo Ihara

Abstract

Understanding the substrate recognition mechanism of γ-secretase is a key step for establishing substrate-specific inhibition of amyloid β-protein (Aβ) production. However, it is widely believed that γ-secretase is a promiscuous protease and that its substrate-specific inhibition is elusive. Here we show that γ-secretase distinguishes the ectodomain length of substrates and preferentially captures and cleaves substrates containing a short ectodomain. We also show that a subset of peptides containing the CDCYCxxxxCxCxSC motif binds to the amino terminus of C99 and inhibits Aβ production in a substrate-specific manner. Interestingly, these peptides suppress β-secretase-dependent cleavage of APP, but not that of sialyltransferase 1. Most importantly, intraperitoneal administration of peptides into mice results in a significant reduction in cerebral Aβ levels. This report provides direct evidence of the substrate preference of γ-secretase and its mechanism. Our results demonstrate that the ectodomain of C99 is a potent target for substrate-specific anti-Aβ therapeutics to combat Alzheimer's disease.

Mentioned in this Paper

Cricetulus
Ectosialyltransferase
Familial Alzheimer Disease (FAD)
HEK293 Cells
APP protein, human
Leukocyte Differentiation Antigens, Human
Proteins, Recombinant DNA
Brain
Chinese Hamster Ovary Cell
Cytokinesis of the Fertilized Ovum

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