RAD50 蛋白通过水解 ATP 将 MRE11 酶从内切核酸酶转换为外切核酸酶。
ATP hydrolysis by RAD50 protein switches MRE11 enzyme from endonuclease to exonuclease.
机构信息
Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, California 94720, USA.
出版信息
J Biol Chem. 2012 Jan 20;287(4):2328-41. doi: 10.1074/jbc.M111.307041. Epub 2011 Nov 18.
Abstract
MRE11-RAD50 is a key early response protein for processing DNA ends of broken chromosomes for repair, yet how RAD50 nucleotide dynamics regulate MRE11 nuclease activity is poorly understood. We report here that ATP binding and ATP hydrolysis cause a striking butterfly-like opening and closing of the RAD50 subunits, and each structural state has a dramatic functional effect on MRE11. RAD50-MRE11 has an extended conformation in solution when MRE11 is an active nuclease. However, ATP binding to RAD50 induces a closed conformation, and in this state MRE11 is an endonuclease. ATP hydrolysis opens the RAD50-MRE11 complex, and MRE11 maintains exonuclease activity. Thus, ATP hydrolysis is a molecular switch that converts MRE11 from an endonuclease to an exonuclease. We propose a testable model in which the open-closed transitions are used by RAD50-MRE11 to discriminate among DNA ends and drive the choice of recombination pathways.
摘要
MRE11-RAD50 是一种关键的早期反应蛋白，用于处理断裂染色体的 DNA 末端以进行修复，但 RAD50 核苷酸动力学如何调节 MRE11 核酸酶活性还知之甚少。我们在这里报告称，ATP 结合和 ATP 水解会导致 RAD50 亚基发生惊人的蝴蝶状开合，每种结构状态对 MRE11 都有显著的功能影响。当 MRE11 是一种活性核酸酶时，RAD50-MRE11 在溶液中具有延伸构象。然而，ATP 结合到 RAD50 会诱导封闭构象，在此状态下，MRE11 是一种内切核酸酶。ATP 水解打开 RAD50-MRE11 复合物，MRE11 保持外切核酸酶活性。因此，ATP 水解是一种分子开关，可将 MRE11 从内切核酸酶转换为外切核酸酶。我们提出了一个可测试的模型，其中 RAD50-MRE11 的开-闭转变用于区分 DNA 末端并驱动重组途径的选择。
相似文献
1
ATP hydrolysis by RAD50 protein switches MRE11 enzyme from endonuclease to exonuclease.RAD50 蛋白通过水解 ATP 将 MRE11 酶从内切核酸酶转换为外切核酸酶。
J Biol Chem. 2012 Jan 20;287(4):2328-41. doi: 10.1074/jbc.M111.307041. Epub 2011 Nov 18.
2
Biochemical characterization of bacteriophage T4 Mre11-Rad50 complex.噬菌体 T4 Mre11-Rad50 复合物的生化特性分析。
J Biol Chem. 2011 Jan 28;286(4):2382-92. doi: 10.1074/jbc.M110.178871. Epub 2010 Nov 15.
3
Structural biochemistry and interaction architecture of the DNA double-strand break repair Mre11 nuclease and Rad50-ATPase.DNA双链断裂修复Mre11核酸酶与Rad50三磷酸腺苷酶的结构生物化学及相互作用结构
Cell. 2001 May 18;105(4):473-85. doi: 10.1016/s0092-8674(01)00335-x.
4
Mre11 and Rad50 from Pyrococcus furiosus: cloning and biochemical characterization reveal an evolutionarily conserved multiprotein machine.嗜热栖热菌的Mre11和Rad50：克隆与生化特性揭示了一种进化上保守的多蛋白机制。
J Bacteriol. 2000 Nov;182(21):6036-41. doi: 10.1128/JB.182.21.6036-6041.2000.
5
Mutation of Conserved Mre11 Residues Alter Protein Dynamics to Separate Nuclease Functions.保守的 Mre11 残基突变改变蛋白动力学以分离核酸酶功能。
J Mol Biol. 2020 May 1;432(10):3289-3308. doi: 10.1016/j.jmb.2020.03.030. Epub 2020 Apr 1.
6
The P. furiosus mre11/rad50 complex promotes 5' strand resection at a DNA double-strand break.激烈火球菌的mre11/rad50复合物在DNA双链断裂处促进5'链切除。
Cell. 2008 Oct 17;135(2):250-60. doi: 10.1016/j.cell.2008.09.054.
7
The rad50 signature motif: essential to ATP binding and biological function.Rad50特征基序：对ATP结合和生物学功能至关重要。
J Mol Biol. 2004 Jan 23;335(4):937-51. doi: 10.1016/j.jmb.2003.11.026.
8
Post-translational methylations of the archaeal Mre11:Rad50 complex throughout the DNA damage response.古菌Mre11:Rad50复合物在整个DNA损伤反应过程中的翻译后甲基化修饰
Mol Microbiol. 2016 Apr;100(2):362-78. doi: 10.1111/mmi.13322. Epub 2016 Feb 19.
9
The characterization of Saccharomyces cerevisiae Mre11/Rad50/Xrs2 complex reveals that Rad50 negatively regulates Mre11 endonucleolytic but not the exonucleolytic activity.酿酒酵母Mre11/Rad50/Xrs2复合物的特性表明，Rad50负向调节Mre11的内切核酸酶活性，但不调节其外切核酸酶活性。
J Mol Biol. 2007 Sep 28;372(4):864-882. doi: 10.1016/j.jmb.2007.07.013. Epub 2007 Jul 21.
10
Rad50 adenylate kinase activity regulates DNA tethering by Mre11/Rad50 complexes.Rad50腺苷酸激酶活性通过Mre11/Rad50复合物调节DNA栓系。
Mol Cell. 2007 Mar 9;25(5):647-61. doi: 10.1016/j.molcel.2007.01.028.
引用本文的文献
1
Dynamic conformations of the P. furiosus MR-DNA complex link Mre11 nuclease activity to DNA-stimulated Rad50 ATP hydrolysis.激烈火球菌MR-DNA复合物的动态构象将Mre11核酸酶活性与DNA刺激的Rad50 ATP水解联系起来。
Commun Biol. 2025 Apr 2;8(1):548. doi: 10.1038/s42003-025-08003-0.
2
Structural features of Dnase1L3 responsible for serum antigen clearance.Dnase1L3 负责血清抗原清除的结构特征。
Commun Biol. 2022 Aug 16;5(1):825. doi: 10.1038/s42003-022-03755-5.
3
Take a Break to Repair: A Dip in the World of Double-Strand Break Repair Mechanisms Pointing the Gaze on Archaea.稍作休息以修复：深入探究双链断裂修复机制——关注古菌。
Int J Mol Sci. 2021 Dec 10;22(24):13296. doi: 10.3390/ijms222413296.
4
Critical DNA damaging pathways in tumorigenesis.肿瘤发生中的关键 DNA 损伤途径。
Semin Cancer Biol. 2022 Oct;85:164-184. doi: 10.1016/j.semcancer.2021.04.012. Epub 2021 Apr 24.
5
DNA end resection and its role in DNA replication and DSB repair choice in mammalian cells.DNA 末端切除及其在哺乳动物细胞中 DNA 复制和 DSB 修复选择中的作用。
Exp Mol Med. 2020 Oct;52(10):1705-1714. doi: 10.1038/s12276-020-00519-1. Epub 2020 Oct 30.
6
Mutation of Conserved Mre11 Residues Alter Protein Dynamics to Separate Nuclease Functions.保守的 Mre11 残基突变改变蛋白动力学以分离核酸酶功能。
J Mol Biol. 2020 May 1;432(10):3289-3308. doi: 10.1016/j.jmb.2020.03.030. Epub 2020 Apr 1.
7
Processing of DNA Double-Strand Breaks by the MRX Complex in a Chromatin Context.染色质环境下MRX复合物对DNA双链断裂的处理
Front Mol Biosci. 2019 Jun 7;6:43. doi: 10.3389/fmolb.2019.00043. eCollection 2019.
8
Purification and Biophysical Characterization of the Mre11-Rad50-Nbs1 Complex.Mre11-Rad50-Nbs1复合物的纯化及生物物理特性分析
Methods Mol Biol. 2019;2004:269-287. doi: 10.1007/978-1-4939-9520-2_20.
9
Stepwise 5' DNA end-specific resection of DNA breaks by the Mre11-Rad50-Xrs2 and Sae2 nuclease ensemble.Mre11-Rad50-Xrs2 和 Sae2 核酸酶复合物对 DNA 断裂进行逐步的 5' DNA 末端特异性切除。
Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5505-5513. doi: 10.1073/pnas.1820157116. Epub 2019 Feb 28.
10
Physical and functional interplay between PCNA DNA clamp and Mre11-Rad50 complex from the archaeon Pyrococcus furiosus.古生菌 Pyrococcus furiosus 中 PCNA 核酸夹与 Mre11-Rad50 复合物的物理和功能相互作用。
Nucleic Acids Res. 2018 Jun 20;46(11):5651-5663. doi: 10.1093/nar/gky322.
本文引用的文献
1
Crystal structure of the Mre11-Rad50-ATPγS complex: understanding the interplay between Mre11 and Rad50.Mre11-Rad50-ATPγS 复合物的晶体结构：解析 Mre11 与 Rad50 之间的相互作用
Genes Dev. 2011 May 15;25(10):1091-104. doi: 10.1101/gad.2037811. Epub 2011 Apr 21.
2
The Mre11:Rad50 structure shows an ATP-dependent molecular clamp in DNA double-strand break repair.Mre11:Rad50 结构显示在 DNA 双链断裂修复中存在一个依赖于 ATP 的分子夹。
Cell. 2011 Apr 1;145(1):54-66. doi: 10.1016/j.cell.2011.02.038.
3
ABC ATPase signature helices in Rad50 link nucleotide state to Mre11 interface for DNA repair.ABC ATPase 特征性螺旋在 Rad50 中连接核苷酸状态与 Mre11 界面以进行 DNA 修复。
Nat Struct Mol Biol. 2011 Apr;18(4):423-31. doi: 10.1038/nsmb.2038. Epub 2011 Mar 27.
4
Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications.DNA 断裂处 DNA 损伤反应蛋白的动力学：聚焦于蛋白修饰。
Genes Dev. 2011 Mar 1;25(5):409-33. doi: 10.1101/gad.2021311.
5
The MRE11 complex: starting from the ends.MRE11 复合物：从末端开始。
Nat Rev Mol Cell Biol. 2011 Feb;12(2):90-103. doi: 10.1038/nrm3047.
6
DNA end resection--unraveling the tail.DNA 末端切除——解开尾巴。
DNA Repair (Amst). 2011 Mar 7;10(3):344-8. doi: 10.1016/j.dnarep.2010.12.004. Epub 2011 Jan 11.
7
Mre11-Rad50-Xrs2 and Sae2 promote 5' strand resection of DNA double-strand breaks.Mre11-Rad50-Xrs2 和 Sae2 促进 DNA 双链断裂的 5' 链切除。
Nat Struct Mol Biol. 2010 Dec;17(12):1478-85. doi: 10.1038/nsmb.1957. Epub 2010 Nov 21.
8
Making the best of the loose ends: Mre11/Rad50 complexes and Sae2 promote DNA double-strand break resection.充分利用松散末端：Mre11/Rad50 复合物和 Sae2 促进 DNA 双链断裂的切除。
DNA Repair (Amst). 2010 Dec 10;9(12):1283-91. doi: 10.1016/j.dnarep.2010.09.015. Epub 2010 Nov 2.
9
Mre11-Rad50-Nbs1 conformations and the control of sensing, signaling, and effector responses at DNA double-strand breaks.Mre11-Rad50-Nbs1 构象与 DNA 双链断裂的感应、信号转导和效应子反应的控制。
DNA Repair (Amst). 2010 Dec 10;9(12):1299-306. doi: 10.1016/j.dnarep.2010.10.001. Epub 2010 Oct 28.
10
Diffusion of the reaction boundary of rapidly interacting macromolecules in sedimentation velocity.快速相互作用的大分子在沉降速度中的反应界面的扩散。
Biophys J. 2010 Jun 2;98(11):2741-51. doi: 10.1016/j.bpj.2010.03.004.
Zotero 插件