Molecular mechanism of the allosteric regulation of the alpha gamma heterodimer of human NAD-dependent isocitrate dehydrogenase

doi:10.1038/srep40921

	Molecular mechanism of the allosteric regulation of the alpha gamma heterodimer of human NAD-dependent isocitrate dehydrogenase
	Ma, Tengfei 1; Peng, Yingjie 1; Huang, Wei 1; Ding, Jianping1,2,3,4
	2017-01-18
发表期刊	SCIENTIFIC REPORTS (IF:3.8[JCR-2023],4.3[5-Year])
ISSN	2045-2322
卷号	7
发表状态	已发表
DOI	10.1038/srep40921
摘要	Human NAD-dependent isocitrate dehydrogenase catalyzes the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate in the Krebs cycle. It exists as the alpha(2)beta gamma heterotetramer composed of the alpha beta and alpha gamma heterodimers. Previously, we have demonstrated biochemically that the alpha(2)beta gamma heterotetramer and alpha gamma heterodimer can be allosterically activated by citrate (CIT) and ADP. In this work, we report the crystal structures of the alpha gamma heterodimer with the gamma subunit bound without or with different activators. Structural analyses show that CIT, ADP and Mg2+ bind adjacent to each other at the allosteric site. The CIT binding induces conformational changes at the allosteric site, which are transmitted to the active site through the heterodimer interface, leading to stabilization of the ICT binding at the active site and thus activation of the enzyme. The ADP binding induces no further conformational changes but enhances the CIT binding through Mg2+-mediated interactions, yielding a synergistic activation effect. ICT can also bind to the CIT-binding subsite, which induces similar conformational changes but exhibits a weaker activation effect. The functional roles of the key residues are verified by mutagenesis, kinetic and structural studies. Our structural and functional data together reveal the molecular mechanism of the allosteric regulation of the alpha gamma heterodimer.
收录类别	SCI
语种	英语
资助项目	Chinese Academy of Sciences[XDB08010302]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000392191000001
出版者	NATURE PUBLISHING GROUP
WOS关键词	PIG-HEART ; OXIDATIVE DAMAGE ; KEY ROLE ; SACCHAROMYCES-CEREVISIAE ; CELLULAR DEFENSE ; KINETIC-ANALYSIS ; BINDING-SITES ; BETA-SUBUNIT ; IDH1 ; MUTATIONS
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1538
专题	生命科学与技术学院_特聘教授组_丁建平组
通讯作者	Ding, Jianping
作者单位	1.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol,Ctr Excellence Mol Cell, Natl Ctr Prot Sci Shanghai,State Key Lab Mol Biol, 320 Yueyang Rd, Shanghai 200031, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China 3.Chinese Acad Sci, Shanghai Sci Res Ctr, 333 Haike Rd, Shanghai 201210, Peoples R China 4.Fudan Univ, Collaborat Innovat Ctr Genet & Dev, 2005 Songhu Rd, Shanghai 200438, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Ma, Tengfei,Peng, Yingjie,Huang, Wei,et al. Molecular mechanism of the allosteric regulation of the alpha gamma heterodimer of human NAD-dependent isocitrate dehydrogenase[J]. SCIENTIFIC REPORTS,2017,7.
APA	Ma, Tengfei,Peng, Yingjie,Huang, Wei,&Ding, Jianping.(2017).Molecular mechanism of the allosteric regulation of the alpha gamma heterodimer of human NAD-dependent isocitrate dehydrogenase.SCIENTIFIC REPORTS,7.
MLA	Ma, Tengfei,et al."Molecular mechanism of the allosteric regulation of the alpha gamma heterodimer of human NAD-dependent isocitrate dehydrogenase".SCIENTIFIC REPORTS 7(2017).