Different Intermolecular Interactions Drive Nonpathogenic Liquid-Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43

doi:10.3390/ijms232315227

	Different Intermolecular Interactions Drive Nonpathogenic Liquid-Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43
	Zeng, Yu-Teng 1; Bi, Lu-Lu1 ; Zhuo, Xiao-Feng1 ; Yang, Ling-Yun2 ; Sun, Bo1 ; Lu, Jun-Xia1
	2022-12-01
发表期刊	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
EISSN	1422-0067
卷号	23 期号:23
发表状态	已发表
DOI	10.3390/ijms232315227
摘要	The liquid-liquid phase separation (LLPS) of proteins has been found ubiquitously in eukaryotic cells, and is critical in the control of many biological processes by forming a temporary condensed phase with different bimolecular components. TDP-43 is recruited to stress granules in cells and is the main component of TDP-43 granules and proteinaceous amyloid inclusions in patients with amyotrophic lateral sclerosis (ALS). TDP-43 low complexity domain (LCD) is able to de-mix in solution, forming the protein condensed droplets, and amyloid aggregates would form from the droplets after incubation. The molecular interactions regulating TDP-43 LCD LLPS were investigated at the protein fusion equilibrium stage, when the droplets stopped growing after incubation. We found the molecules in the droplet were still liquid-like, but with enhanced intermolecular helix-helix interactions. The protein would only start to aggregate after a lag time and aggregate slower than at the condition when the protein does not phase separately into the droplets, or the molecules have a reduced intermolecular helix-helix interaction. In the protein condensed droplets, a structural transition intermediate toward protein aggregation was discovered involving a decrease in the intermolecular helix-helix interaction and a reduction in the helicity. Our results therefore indicate that different intermolecular interactions drive LLPS and fibril formation. The discovery that TDP-43 LCD aggregation was faster through the pathway without the first protein phase separation supports that LLPS and the intermolecular helical interaction could help maintain the stability of TDP-43 LCD.
关键词	TDP-43 liquid-liquid phase separation solution-state NMR
URL	查看原文
收录类别	SCI
语种	英语
资助项目	Natural Science Foundation of China["32171185","31770790","21904088"] ; National Key Research and Development Program of China[2017YFA0504804]
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
WOS类目	Biochemistry & Molecular Biology ; Chemistry, Multidisciplinary
WOS记录号	WOS:000897322400001
出版者	MDPI
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/266609
专题	生命科学与技术学院_PI研究组_孙博组生命科学与技术学院_PI研究组_陆珺霞组 iHuman研究所_公共科研平台_生命科学NMR平台生命科学与技术学院_硕士生
通讯作者	Lu, Jun-Xia
作者单位	1.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 2.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
第一作者单位	生命科学与技术学院
通讯作者单位	生命科学与技术学院
第一作者的第一单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Zeng, Yu-Teng,Bi, Lu-Lu,Zhuo, Xiao-Feng,et al. Different Intermolecular Interactions Drive Nonpathogenic Liquid-Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43[J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,2022,23(23).
APA	Zeng, Yu-Teng,Bi, Lu-Lu,Zhuo, Xiao-Feng,Yang, Ling-Yun,Sun, Bo,&Lu, Jun-Xia.(2022).Different Intermolecular Interactions Drive Nonpathogenic Liquid-Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43.INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,23(23).
MLA	Zeng, Yu-Teng,et al."Different Intermolecular Interactions Drive Nonpathogenic Liquid-Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43".INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 23.23(2022).