Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion

	Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion
	Jiang, LL; Che, MX; Zhao, J; Zhou, CJ; Xie, MY; Li, HY; He, JH; Hu, HY
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2013
卷号	288 期号:27 页码:19614-19624
通讯作者	Hu, HY (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai 200031, Peoples R China.,hyhu@sibcb.ac.cn
英文摘要	TDP-43 (TAR DNA-binding protein of 43 kDa) is a major deposited protein in amyotrophic lateral sclerosis and frontotemporal dementia with ubiquitin. A great number of genetic mutations identified in the flexible C-terminal region are associated with disease pathologies. We investigated the molecular determinants of TDP-43 aggregation and its underlying mechanisms. We identified a hydrophobic patch (residues 318-343) as the amyloidogenic core essential for TDP-43 aggregation. Biophysical studies demonstrated that the homologous peptide formed a helix-turn-helix structure in solution, whereas it underwent structural transformation from an alpha-helix to a beta-sheet during aggregation. Mutation or deletion of this core region significantly reduced the aggregation and cytoplasmic inclusions of full-length TDP-43 (or TDP-35 fragment) in cells. Thus, structural transformation of the amyloidogenic core initiates the aggregation and cytoplasmic inclusion formation of TDP-43. This particular core region provides a potential therapeutic target to design small-molecule compounds for mitigating TDP-43 proteinopathies.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	AMYOTROPHIC-LATERAL-SCLEROSIS ; FRONTOTEMPORAL LOBAR DEGENERATION ; ALZHEIMERS A-BETA-42 PEPTIDE ; HUMAN ALPHA-SYNUCLEIN ; FIBRIL FORMATION ; SPLICING REGULATION ; TERMINAL FRAGMENTS ; RNA DEPLETION ; HUMAN-DISEASE ; MUTATIONS
收录类别	SCI
语种	英语
WOS记录号	WOS:000321515800027
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/470]
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	Jiang, LL,Che, MX,Zhao, J,et al. Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2013,288(27):19614-19624.
APA	Jiang, LL.,Che, MX.,Zhao, J.,Zhou, CJ.,Xie, MY.,...&Hu, HY.(2013).Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion.JOURNAL OF BIOLOGICAL CHEMISTRY,288(27),19614-19624.
MLA	Jiang, LL,et al."Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion".JOURNAL OF BIOLOGICAL CHEMISTRY 288.27(2013):19614-19624.