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Alternative Selection of beta-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid beta-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the A beta Sequence

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タイトル: Alternative Selection of beta-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid beta-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the A beta Sequence
著者: Kimura, Ayano 著作を一覧する
Hata, Saori 著作を一覧する
Suzuki, Toshiharu 著作を一覧する
キーワード: Alzheimer disease
amyloid precursor protein (APP)
amyloid-β (Aβ)
β-secretase 1 (BACE1)
secretase
発行日: 2016年11月11日
出版者: American Society for Biochemistry and Molecular Biology (ASBMB)
誌名: Journal of Biological Chemistry (JBC)
巻: 291
号: 46
開始ページ: 24041
終了ページ: 24053
出版社 DOI: 10.1074/jbc.M116.744722
抄録: beta-Site APP-cleaving enzyme 1 (BACE1) cleaves amyloid -protein precursor (APP) at the bond between Met(671) and Asp(672) (-site) to generate the carboxyl-terminal fragment (CTF/C99). BACE1 also cleaves APP at another bond between Thr(681) and Gln(682) (-site), yielding CTF/C89. Cleavage of CTF/C99 by -secretase generates A(1-XX), whereas cleavage of CTF/C89 generates A(11-XX). Thus, -site cleavage by BACE1 is amyloidolytic rather than amyloidogenic. cleavage of mouse APP is more common than the corresponding cleavage of human APP. We found that the H684R substitution within human A, which replaces the histidine in the human protein with the arginine found at the corresponding position in mouse, facilitated cleavage irrespective of the species origin of BACE1, thereby significantly increasing the level of A(11-XX) and decreasing the level of A(1-XX). Thus, amino acid substitutions within the A sequence influenced the selectivity of alternative - or -site cleavage of APP by BACE1. In familial Alzheimer's disease (FAD), the APP gene harbors pathogenic variations such as the Swedish (K670N/M671L), Leuven (E682K), and A673V mutations, all of which decrease A(11-40) generation, whereas the protective Icelandic mutation (A673T) increases generation of A(11-40). Thus, A673T promotes cleavage of APP and protects subjects against AD. In addition, CTF/C99 was cleaved by excess BACE1 activity to generate CTF/C89, followed by A(11-40), even if APP harbored pathogenic mutations. The resultant A(11-40) was more metabolically labile in vivo than A(1-40). Our analysis suggests that some FAD mutations in APP are amyloidogenic and/or amyloidolytic via selection of alternative BACE1 cleavage sites.
Rights: This research was originally published in The journal of biological chemistry. Ayano Kimura, Saori Hata and Toshiharu Suzuki. Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the Aβ Sequence. The journal of biological chemistry. 2016; Vol.291:24041-24053. ©the American Society for Biochemistry and Molecular Biology
資料タイプ: article (author version)
URI: http://hdl.handle.net/2115/67573
出現コレクション:雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

提供者: 鈴木 利治

 

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