Structural insight into substrate preference for TET- mediated oxidation

doi:10.1038/nature15713

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Structural insight into substrate preference for TET- mediated oxidation
	Hu, Lulu 4,5,6; Lu, Junyan 7; Cheng, Jingdong 4,5; Rao, Qinhui 4,5; Li, Ze 4,5; Hou, Haifeng 8; Lou, Zhiyong 9,10; Zhang, Lei 4,5; Li, Wei 4; Gong, Wei 4,5
刊名	NATURE
	2015-11-05
卷号	527 期号:7576 页码:118-122
ISSN号	0028-0836
DOI	10.1038/nature15713
文献子类	Article
英文摘要	DNA methylation is an important epigenetic modification(1-3). Ten-eleven translocation (TET) proteins are involved in DNA demethylation through iteratively oxidizing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC)(4-8). Here we show that human TET1 and TET2 are more active on 5mC-DNA than 5hmC/5fC-DNA substrates. We determine the crystal structures of TET2-5hmC-DNA and TET2-5fC-DNA complexes at 1.80 angstrom and 1.97 angstrom resolution, respectively. The cytosine portion of 5hmC/5fC is specifically recognized by TET2 in a manner similar to that of 5mC in the TET2-5mC-DNA structure(9), and the pyrimidine base of 5mC/5hmC/5fC adopts an almost identical conformation within the catalytic cavity. However, the hydroxyl group of 5hmC and carbonyl group of 5fC face towards the opposite direction because the hydroxymethyl group of 5hmC and formyl group of 5fC adopt restrained conformations through forming hydrogen bonds with the 1-carboxylate of NOG and N4 exocyclic nitrogen of cytosine, respectively. Biochemical analyses indicate that the substrate preference of TET2 results from the different efficiencies of hydrogen abstraction in TET2-mediated oxidation. The restrained conformation of 5hmC and 5fC within the catalytic cavity may prevent their abstractable hydrogen(s) adopting a favourable orientation for hydrogen abstraction and thus result in low catalytic efficiency. Our studies demonstrate that the substrate preference of TET2 results from the intrinsic value of its substrates at their 5mC derivative groups and suggest that 5hmC is relatively stable and less prone to further oxidation by TET proteins. Therefore, TET proteins are evolutionarily tuned to be less reactive towards 5hmC and facilitate the generation of 5hmC as a potentially stable mark for regulatory functions.
资助项目	National Basic Research Program of China[2011CB965300] ; National Science & Technology Major Project 'Key New Drug Creation and Manufacturing Program' of China[2014ZX09507-002] ; National Natural Science Foundation of China[U1432242] ; National Natural Science Foundation of China[31425008] ; National Natural Science Foundation of China[91419301] ; National Natural Science Foundation of China[91313000] ; National Natural Science Foundation of China[31270779] ; National Natural Science Foundation of China[21210003] ; Basic Research Project of Shanghai Science and Technology Commission[12JC1402700] ; Program of Shanghai Subject Chief Scientist[14XD1400500] ; Hi-Tech Research and Development Program of China[2012AA020302] ; Hi-Tech Research and Development Program of China[2012AA01A305] ; Chinese Academy of Sciences[XDA01040305]
WOS关键词	MAMMALIAN DNA ; 5-FORMYLCYTOSINE ; GENOME ; 5-HYDROXYMETHYLCYTOSINE ; 5-CARBOXYLCYTOSINE ; 5-METHYLCYTOSINE ; DEMETHYLATION ; REVEALS ; ROLES ; ALKB
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000364270700055
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276331]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Xu, Yanhui
作者单位	1.Univ Chicago, Dept Chem, Chicago, IL 60637 USA; 2.Univ Chicago, Howard Hughes Med Inst, Chicago, IL 60637 USA 3.Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA; 4.Fudan Univ, Shanghai Med Coll, Inst Biomed Sci, Shanghai Canc Ctr, Shanghai 200032, Peoples R China; 5.Fudan Univ, Shanghai Med Coll, Sch Basic Med Sci, Key Lab Mol Med,Minist Educ,Dept Syst Biol Med, Shanghai 200032, Peoples R China; 6.Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai 200433, Peoples R China; 7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; 8.Chinese Acad Sci, Inst High Energy Phys, Beijing Synchrotron Radiat Facil, Beijing 100049, Peoples R China; 9.Tsinghua Univ, Lab Struct Biol, Beijing 100084, Peoples R China; 10.Tsinghua Univ, Sch Med, MOE Lab Prot Sci, Beijing 100084, Peoples R China;
推荐引用方式 GB/T 7714	Hu, Lulu,Lu, Junyan,Cheng, Jingdong,et al. Structural insight into substrate preference for TET- mediated oxidation[J]. NATURE,2015,527(7576):118-122.
APA	Hu, Lulu.,Lu, Junyan.,Cheng, Jingdong.,Rao, Qinhui.,Li, Ze.,...&Xu, Yanhui.(2015).Structural insight into substrate preference for TET- mediated oxidation.NATURE,527(7576),118-122.
MLA	Hu, Lulu,et al."Structural insight into substrate preference for TET- mediated oxidation".NATURE 527.7576(2015):118-122.