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

Satoru Funamoto (), Toru Sasaki, Seiko Ishihara, Mika Nobuhara, Masaki Nakano, Miho Watanabe-Takahashi, Takashi Saito, Nobuto Kakuda, Tomohiro Miyasaka, Kiyotaka Nishikawa, Takaomi C. Saido and Yasuo Ihara
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Satoru Funamoto: Graduate School of Life and Medical Sciences, Doshisha University
Toru Sasaki: Core Research for Evolutional Science and Technology, Japan Science and Technology Agency
Seiko Ishihara: Graduate School of Life and Medical Sciences, Doshisha University
Mika Nobuhara: Graduate School of Life and Medical Sciences, Doshisha University
Masaki Nakano: Graduate School of Life and Medical Sciences, Doshisha University
Miho Watanabe-Takahashi: Graduate School of Life and Medical Sciences, Doshisha University
Takashi Saito: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute
Nobuto Kakuda: Core Research for Evolutional Science and Technology, Japan Science and Technology Agency
Tomohiro Miyasaka: Graduate School of Life and Medical Sciences, Doshisha University
Kiyotaka Nishikawa: Graduate School of Life and Medical Sciences, Doshisha University
Takaomi C. Saido: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute
Yasuo Ihara: Core Research for Evolutional Science and Technology, Japan Science and Technology Agency

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3529

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