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Nat Commun. 2013;4:2529. doi: 10.1038/ncomms3529.

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

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1] Department of Neuropathology, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan [2] Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0076, Japan.


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.

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