Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH

	Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH
	Dang, SY; Wu, SJ; Wang, JW; Li, HB; Huang, M; He, W; Li, YM; Wong, CCL; Shi, YG
刊名	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
	2015
卷号	112 期号:11 页码:3344-3349
关键词	intramembrane protease Alzheimer's disease PSH gamma-secretase beta-amyloid peptide
通讯作者	Shi, YG (reprint author), Tsinghua Univ, Sch Life Sci, Minist Educ, Key Lab Prot Sci, Beijing 100084, Peoples R China.,shi-lab@tsinghua.edu.cn
英文摘要	Aberrant cleavage of amyloid precursor protein (APP) by gamma-secretase contributes to the development of Alzheimer's disease. More than 200 disease-derived mutations have been identified in presenilin (the catalytic subunit of gamma-secretase), making modulation of gamma-secretase activity a potentially attractive therapeutic opportunity. Unfortunately, the technical challenges in dealing with intact gamma-secretase have hindered discovery of modulators and demand a convenient substitute approach. Here we report that, similar to gamma-secretase, the archaeal presenilin homolog PSH faithfully processes the substrate APP C99 into A beta 42, A beta 40, and A beta 38. The molar ratio of the cleavage products A beta 42 over A beta 40 by PSH is nearly identical to that by gamma-secretase. The proteolytic activity of PSH is specifically suppressed by presenilin-specific inhibitors. Known modulators of gamma-secretase also modulate PSH similarly in terms of the A beta 42/A beta 40 ratio. Structural analysis reveals association of a known gamma-secretase inhibitor with PSH between its two catalytic aspartate residues. These findings identify PSH as a surrogate protease for the screening of agents that may regulate the protease activity and the cleavage preference of gamma-secretase.
学科主题	Science & Technology - Other Topics
类目[WOS]	Multidisciplinary Sciences
关键词[WOS]	FAMILIAL ALZHEIMER-DISEASE ; GAMMA-SECRETASE MODULATORS ; SPASTIC PARAPARESIS ; DIFFERENT MECHANISMS ; A-BETA ; MUTATIONS ; NICASTRIN ; INHIBITORS
收录类别	SCI
语种	英语
WOS记录号	WOS:000351060000063
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/93]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Dang, SY,Wu, SJ,Wang, JW,et al. Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2015,112(11):3344-3349.
APA	Dang, SY.,Wu, SJ.,Wang, JW.,Li, HB.,Huang, M.,...&Shi, YG.(2015).Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,112(11),3344-3349.
MLA	Dang, SY,et al."Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 112.11(2015):3344-3349.