Substrate ectodomain is critical for substrate preference and inhibition of γ-secretase.
Substrate ectodomain is critical for substrate preference and inhibition of γ-secretase.
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底物外域对底物偏好和抑制γ-分泌酶至关重要。
DOI：
10.1038/ncomms3529
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发表时间：
2013
影响因子：
16.6
通讯作者：
Ihara, Yasuo
中科院分区：
文献类型：
--
作者：
Funamoto, Satoru;Sasaki, Toru;Ishihara, Seiko;Nobuhara, Mika;Nakano, Masaki;Watanabe-Takahashi, Miho;Saito, Takashi;Kakuda, Nobuto;Miyasaka, Tomohiro;Nishikawa, Kiyotaka;Saido, Takaomi C.;Ihara, Yasuo
了解γ-分泌酶的底物识别机制是建立底物特异性抑制淀粉样蛋白β (a β)产生的关键步骤。然而，人们普遍认为γ-分泌酶是一种混杂的蛋白酶，其底物特异性抑制是难以捉摸的。我们发现γ-分泌酶能够区分底物的外畴长度，并优先捕获和切割含有短外畴的底物。我们还发现含有CDCYCxxxxCxCxSC基序的肽亚群与C99的氨基末端结合，并以底物特异性的方式抑制a β的产生。有趣的是，这些肽抑制β-分泌酶依赖性的APP裂解，但不抑制唾液基转移酶1。最重要的是，小鼠腹腔内注射多肽可显著降低大脑a β水平。本报告为γ-分泌酶的底物偏好及其机制提供了直接证据。我们的研究结果表明，C99的外畴是抗阿尔茨海默病的底物特异性抗β治疗的有效靶点。γ-分泌酶抑制剂被研究用于治疗阿尔茨海默病的潜力，但其使用受到副作用的限制。Funamoto等人表明，γ-分泌酶优先切割具有短外结构域的底物，并且基于这些外结构域的抑制剂可减少小鼠的疾病样病理。
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. γ-Secretase inhibitors are studied for their potential to treat Alzheimer’s disease, but their use is limited by side effects. Funamoto et al. show that γ-secretase preferentially cleaves substrates with short ectodomains and that inhibitors based on these ectodomains reduce disease-like pathology in mice.
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影响因子：
2.9
作者：
Funamoto, S;Morshima-Kawashima, M;Ihara, Y
通讯作者：
Ihara, Y
影响因子：
82.9
作者：
Kukar, T;Murphy, MP;Golde, TE
通讯作者：
Golde, TE
影响因子：
64.8
作者：
De Strooper, B;Saftig, P;Van Leuven, F
通讯作者：
Van Leuven, F
影响因子：
11.2
作者：
Hata, Saori;Fujishige, Sayaka;Araki, Yoichi;Taniguchi, Miyako;Urakami, Katsuya;Peskind, Elaine;Akatsu, Hiroyasu;Araseki, Masahiko;Yamamoto, Kazuo;Martins, Ralph N.;Maeda, Masahiro;Nishimura, Masaki;Levey, Allan;Chung, Kathryn A.;Montine, Thomas;Leverenz, James;Fagan, Anne;Goate, Alison;Bateman, Randall;Holtzman, David M.;Yamamoto, Tohru;Nakaya, Tadashi;Gandy, Sam;Suzuki, Toshiharu
通讯作者：
Suzuki, Toshiharu
影响因子：
4.8
作者：
Hata, Saori;Fujishige, Sayaka;Suzuki, Toshiharu
通讯作者：
Suzuki, Toshiharu