Deciphering the role of dimer interface in intrinsic dynamics and allosteric pathways underlying the functional transformation of DNMT3A
文献类型：期刊论文
| 作者 | Liang, Zhongjie2; Hu, Junchi1,3; Yan, Wenying2; Jiang, Hualiang3 ; Hu, Guang2; Luo, Cheng3
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| 刊名 | BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
 |
| 出版日期 | 2018-07 |
| 卷号 | 1862期号:7页码:1667-1679 |
| 关键词 | Conformational dynamics Allosteric communication Elastic network models, network theory, coevolution analysis |
| ISSN号 | 0304-4165 |
| DOI | 10.1016/j.bbagen.2018.04.0.15 |
| 文献子类 | Article |
| 英文摘要 | Background: DNMT3A, as de novo DNA methyltransferase, is essential for regulating gene expression through cellular development and differentiation. The functions of DNMT3A rely on its oligomeric states and allosteric regulations between its catalytic domain and binding partners. Despite recent resolution of autoinhibitory and active DNMT3A/3L crystal structures, the mechanism of their functional motions and interdomain allostery in regulating the activity remains to be established. Methods: The hybrid approach, comprising Elastic Network Models coupled with information theory, Protein Structure Network, and sequence evolution analysis was employed to investigate intrinsic dynamics and allosteric properties of DNMT3A resolved in autoinhibitory and active states. Results: The conformational transition between two states is characterized by global motions, and the homodimer displays the similar dynamic properties as tetramer, acting as the basic functional unit. The hinge residues with restricted fluctuations are clustered at the dimer interface, which are predicted to enjoy remarkably efficient signal transduction properties. The allosteric pathways through the dimer interface are achieved by a cascade of interactions predominantly involving conserved and co-evolved residues. Conclusions: Our results suggest that structural topology coupled with global motions indicates the structural origin of the functional transformation of DNMT3A. The comprehensive analysis further highlights the pivotal role of the dimer interface of DNMT3A both in defining the quatemary structure dynamics and establishing interdomain communications. General significance: Understanding the global motions of DNMT3As not only provides mechanical insights into the functions of such molecular machines, but also reveals the mediators that determine their allosteric regulations. |
| WOS关键词 | METHYLTRANSFERASE GENE DNMT3A ; NOVO DNA METHYLATION ; PROTEIN STRUCTURES ; BIOMOLECULAR SYSTEMS ; STRUCTURAL DYNAMICS ; SEQUENCE EVOLUTION ; GLOBAL DYNAMICS ; MECHANISM ; BINDING ; NETWORK |
| 资助项目 | Computer Network Information Center, Chinese Academy of Sciences and Tianjin Supercomputing Center[00000000] ; China Postdoctoral Science Foundation[2013M531406] ; China Postdoctoral Science Foundation[2016M590495] ; National Natural Science Foundation of China[31600671] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Biophysics |
| 语种 | 英语 |
| WOS记录号 | WOS:000434888900015 |
| 出版者 | ELSEVIER SCIENCE BV |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279690]  |
| 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 | Hu, Guang; Luo, Cheng |
| 作者单位 | 1.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 2.Soochow Univ, Ctr Syst Biol, Suzhou 215006, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res,State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Liang, Zhongjie,Hu, Junchi,Yan, Wenying,et al. Deciphering the role of dimer interface in intrinsic dynamics and allosteric pathways underlying the functional transformation of DNMT3A[J]. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS,2018,1862(7):1667-1679. |
| APA | Liang, Zhongjie,Hu, Junchi,Yan, Wenying,Jiang, Hualiang,Hu, Guang,&Luo, Cheng.(2018).Deciphering the role of dimer interface in intrinsic dynamics and allosteric pathways underlying the functional transformation of DNMT3A.BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS,1862(7),1667-1679. |
| MLA | Liang, Zhongjie,et al."Deciphering the role of dimer interface in intrinsic dynamics and allosteric pathways underlying the functional transformation of DNMT3A".BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS 1862.7(2018):1667-1679. |
入库方式： OAI收割
来源：上海药物研究所
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