Dimerization of the transmembrane domain of amyloid precursor protein is determined by residues around the gamma - secretase cleavage sites

doi:10.1074/jbc.M117.789669

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	Dimerization of the transmembrane domain of amyloid precursor protein is determined by residues around the gamma - secretase cleavage sites
	Yan, Yan 2,3,4; Xu, Ting-Hai 2,3,4; Harikumar, Kaleeckal G.1; Miller, Laurence J.1; Melcher, Karsten 4; Xu, H. Eric3,4
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2017-09-22
卷号	292 期号:38 页码:15826-15837
ISSN号	0021-9258
DOI	10.1074/jbc.M117.789669
文献子类	Article
英文摘要	One of the hallmarks of Alzheimer's disease is the formation of extracellular amyloid plaques that consist mainly of abnormally aggregated forms of amyloid beta (A beta) peptides. These peptides are generated by gamma-secretase-catalyzed cleavage of a dimeric membrane-bound C-terminal fragment (C99) of the amyloid precursor protein. Although C99 homodimerization has been linked to A beta production and changes in the aggregation-determining A beta 42/40 ratio, the motif through which C99 dimerizes has remained controversial. Here, we have used two independent assays to gain insight in to C99homodimerization in the context of the membrane of live cells: bioluminescence resonance energy transfer and Tango membrane proteinprotein interaction assays, which were further confirmed by traditional pull-down assays. Our results indicate a four-amino acid region within the C99 transmembrane helix (43TVIV46) as well as its local secondary structure as critical determinants for homodimerization. These four amino acids are also a hot spot of familial Alzheimer's disease-linked mutations that both decrease C99 homodimerization and gamma-secretase cleavage and alter the initial cleavage site to increase the A beta 42/40 ratio.
资助项目	NIGMS NIH HHS[R01 GM104212] ; NIGMS NIH HHS[R01 GM102545] ; NIDDK NIH HHS[R01 DK071662]
WOS关键词	C-TERMINAL DOMAIN ; ALZHEIMERS-DISEASE ; APP DIMERIZATION ; COUPLED SECRETIN ; GXXXG MOTIFS ; HOMODIMERIZATION ; DIMER ; BETA ; OLIGOMERIZATION ; DUPLICATION
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
WOS记录号	WOS:000411512200020
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272479]
专题	药物靶标结构与功能中心
通讯作者	Melcher, Karsten; Xu, H. Eric
作者单位	1.Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Scottsdale, AZ 85259 USA 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, VARI SIMM Ctr, Key Lab Receptor Res, Shanghai 201203, Peoples R China; 4.Van Andel Res Inst, Innovat & Integrat Program, Ctr Canc & Cell Biol, Grand Rapids, MI 49503 USA;
推荐引用方式 GB/T 7714	Yan, Yan,Xu, Ting-Hai,Harikumar, Kaleeckal G.,et al. Dimerization of the transmembrane domain of amyloid precursor protein is determined by residues around the gamma - secretase cleavage sites[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2017,292(38):15826-15837.
APA	Yan, Yan,Xu, Ting-Hai,Harikumar, Kaleeckal G.,Miller, Laurence J.,Melcher, Karsten,&Xu, H. Eric.(2017).Dimerization of the transmembrane domain of amyloid precursor protein is determined by residues around the gamma - secretase cleavage sites.JOURNAL OF BIOLOGICAL CHEMISTRY,292(38),15826-15837.
MLA	Yan, Yan,et al."Dimerization of the transmembrane domain of amyloid precursor protein is determined by residues around the gamma - secretase cleavage sites".JOURNAL OF BIOLOGICAL CHEMISTRY 292.38(2017):15826-15837.