文献检索文档翻译深度研究
Suppr Zotero 插件Zotero 插件
邀请有礼套餐&价格历史记录

新学期，新优惠

限时优惠:9月1日-9月22日

30天高级会员仅需29元

1天体验卡首发特惠仅需5.99元

了解详情
不再提醒
插件&应用
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
高级版
套餐订阅购买积分包
AI 工具
文献检索文档翻译深度研究
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2025

甲基-CpG结合域蛋白2（MBD2）的一个内在无序区域募集了核小体重塑去乙酰化酶（NuRD）复合物的组蛋白去乙酰化酶核心。

An intrinsically disordered region of methyl-CpG binding domain protein 2 (MBD2) recruits the histone deacetylase core of the NuRD complex.

作者信息

Desai Megha A, Webb Heather D, Sinanan Leander M, Scarsdale J Neel, Walavalkar Ninad M, Ginder Gordon D, Williams David C

机构信息

Department of Human and Molecular Genetics and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.

Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.

出版信息

Nucleic Acids Res. 2015 Mar 31;43(6):3100-13. doi: 10.1093/nar/gkv168. Epub 2015 Mar 9.

DOI:10.1093/nar/gkv168
PMID:25753662
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4381075/
Abstract

The MBD2-NuRD (Nucleosome Remodeling and Deacetylase) complex is an epigenetic reader of DNA methylation that regulates genes involved in normal development and neoplastic diseases. To delineate the architecture and functional interactions of the MBD2-NuRD complex, we previously solved the structures of MBD2 bound to methylated DNA and a coiled-coil interaction between MBD2 and p66α that recruits the CHD4 nucleosome remodeling protein to the complex. The work presented here identifies novel structural and functional features of a previously uncharacterized domain of MBD2 (MBD2IDR). Biophysical analyses show that the MBD2IDR is an intrinsically disordered region (IDR). However, despite this inherent disorder, MBD2IDR increases the overall binding affinity of MBD2 for methylated DNA. MBD2IDR also recruits the histone deacetylase core components (RbAp48, HDAC2 and MTA2) of NuRD through a critical contact region requiring two contiguous amino acid residues, Arg(286) and Leu(287). Mutating these residues abrogates interaction of MBD2 with the histone deacetylase core and impairs the ability of MBD2 to repress the methylated tumor suppressor gene PRSS8 in MDA-MB-435 breast cancer cells. These findings expand our knowledge of the multi-dimensional interactions of the MBD2-NuRD complex that govern its function.

摘要

MBD2-NuRD（核小体重塑与去乙酰化酶）复合物是一种DNA甲基化的表观遗传阅读器，可调节参与正常发育和肿瘤疾病的基因。为了描绘MBD2-NuRD复合物的结构和功能相互作用，我们之前解析了与甲基化DNA结合的MBD2的结构，以及MBD2与p66α之间的卷曲螺旋相互作用，该相互作用将CHD4核小体重塑蛋白招募到复合物中。本文介绍的工作确定了MBD2一个先前未被表征的结构域（MBD2IDR）的新结构和功能特征。生物物理分析表明，MBD2IDR是一个内在无序区域（IDR）。然而，尽管存在这种内在无序，MBD2IDR却增加了MBD2对甲基化DNA的整体结合亲和力。MBD2IDR还通过一个需要两个相邻氨基酸残基Arg(286)和Leu(287)的关键接触区域招募NuRD的组蛋白去乙酰化酶核心成分（RbAp48、HDAC2和MTA2）。突变这些残基会消除MBD2与组蛋白去乙酰化酶核心的相互作用，并损害MBD2在MDA-MB-435乳腺癌细胞中抑制甲基化肿瘤抑制基因PRSS8的能力。这些发现扩展了我们对控制其功能的MBD2-NuRD复合物多维相互作用的认识。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b6/4381075/5ad9b02ae848/gkv168fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b6/4381075/bad11469c027/gkv168fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b6/4381075/d7a27337d147/gkv168fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b6/4381075/88ca0a26caab/gkv168fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b6/4381075/5b08a0b23746/gkv168fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b6/4381075/e38b14d43ade/gkv168fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b6/4381075/5ad9b02ae848/gkv168fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b6/4381075/bad11469c027/gkv168fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b6/4381075/d7a27337d147/gkv168fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b6/4381075/88ca0a26caab/gkv168fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b6/4381075/5b08a0b23746/gkv168fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b6/4381075/e38b14d43ade/gkv168fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b6/4381075/5ad9b02ae848/gkv168fig6.jpg

相似文献

[1]
An intrinsically disordered region of methyl-CpG binding domain protein 2 (MBD2) recruits the histone deacetylase core of the NuRD complex.

Nucleic Acids Res. 2015-3-31

[2]
MBD2 and multiple domains of CHD4 are required for transcriptional repression by Mi-2/NuRD complexes.

Mol Cell Biol. 2012-10-15

[3]
Unique features of the anti-parallel, heterodimeric coiled-coil interaction between methyl-cytosine binding domain 2 (MBD2) homologues and GATA zinc finger domain containing 2A (GATAD2A/p66α).

J Biol Chem. 2012-12-13

[4]
MBD3L2 interacts with MBD3 and components of the NuRD complex and can oppose MBD2-MeCP1-mediated methylation silencing.

J Biol Chem. 2005-4-1

[5]
Analysis of the complex between MBD2 and the histone deacetylase core of NuRD reveals key interactions critical for gene silencing.

Proc Natl Acad Sci U S A. 2023-8-15

[6]
Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation.

Genes Dev. 1999-8-1

[7]
p66Alpha-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex.

Proc Natl Acad Sci U S A. 2011-4-13

[8]
Disruption of the MBD2-NuRD complex but not MBD3-NuRD induces high level HbF expression in human adult erythroid cells.

Haematologica. 2019-4-19

[9]
CpG and methylation-dependent DNA binding and dynamics of the methylcytosine binding domain 2 protein at the single-molecule level.

Nucleic Acids Res. 2017-9-6

[10]
MBD3L1 is a transcriptional repressor that interacts with methyl-CpG-binding protein 2 (MBD2) and components of the NuRD complex.

J Biol Chem. 2004-12-10

引用本文的文献

[1]
Removal of promoter CpG methylation by epigenome editing reverses HBG silencing.

Nat Commun. 2025-7-27

[2]
An intrinsically disordered region of histone demethylase KDM5A activates catalysis through interactions with the nucleosomal acidic patch and DNA.

bioRxiv. 2025-5-2

[3]
Exploring the bistable equilibrium of methylated CpG DNA recognition by the MBD2 protein.

bioRxiv. 2025-6-30

[4]
The role of multivalency in the association of the eight twenty-one protein 2 (ETO2) with the nucleosome remodeling and deacetylase (NuRD) complex.

Nucleic Acids Res. 2025-5-22

[5]
Uncovering the Molecular Interactions Underlying MBD2 and MBD3 Phase Separation.

J Phys Chem B. 2025-6-12

[6]
Targeting redox-sensitive MBD2-NuRD condensate in cancer cells.

Nat Cell Biol. 2025-5

[7]
Versatile functions of methyl-CpG-binding domain 2 (MBD2) in cellular characteristics and differentiation.

Mol Biol Rep. 2025-3-15

[8]
Epigenetics-targeted drugs: current paradigms and future challenges.

Signal Transduct Target Ther. 2024-11-26

[9]
MBD2 regulates the progression and chemoresistance of cholangiocarcinoma through interaction with WDR5.

J Exp Clin Cancer Res. 2024-9-30

[10]
MTA2 knockdown suppresses human osteosarcoma metastasis by inhibiting uPA expression.

Aging (Albany NY). 2024-9-6

本文引用的文献

[1]
Solution structure and intramolecular exchange of methyl-cytosine binding domain protein 4 (MBD4) on DNA suggests a mechanism to scan for mCpG/TpG mismatches.

Nucleic Acids Res. 2014

[2]
Towards elucidating the stability, dynamics and architecture of the nucleosome remodeling and deacetylase complex by using quantitative interaction proteomics.

FEBS J. 2015-5

[3]
Insight into the architecture of the NuRD complex: structure of the RbAp48-MTA1 subcomplex.

J Biol Chem. 2014-8-8

[4]
Targeting the disordered C terminus of PTP1B with an allosteric inhibitor.

Nat Chem Biol. 2014-5-20

[5]
Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells.

Cell Stem Cell. 2014-7-3

[6]
Transcriptional repressor domain of MBD1 is intrinsically disordered and interacts with its binding partners in a selective manner.

Sci Rep. 2014-5-9

[7]
Targeting the intrinsically disordered structural ensemble of α-synuclein by small molecules as a potential therapeutic strategy for Parkinson's disease.

PLoS One. 2014-2-14

[8]
Probing the dynamic distribution of bound states for methylcytosine-binding domains on DNA.

J Biol Chem. 2013-12-4

[9]
Transcription onset of genes critical in liver carcinogenesis is epigenetically regulated by methylated DNA-binding protein MBD2.

Carcinogenesis. 2013-8-16

[10]
Class I HDACs share a common mechanism of regulation by inositol phosphates.

Mol Cell. 2013-6-20

文献AI研究员

20分钟写一篇综述，助力文献阅读效率提升50倍

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

推荐工具

医学文档翻译智能文献检索