Ero1α 中的一种新型二硫键开关机制平衡了人类细胞中的内质网氧化作用。
A novel disulphide switch mechanism in Ero1alpha balances ER oxidation in human cells.
作者信息
Appenzeller-Herzog Christian, Riemer Jan, Christensen Brian, Sørensen Esben S, Ellgaard Lars
机构信息
Department of Biology, University of Copenhagen, Copenhagen Ø, Denmark.
出版信息
EMBO J. 2008 Nov 19;27(22):2977-87. doi: 10.1038/emboj.2008.202. Epub 2008 Oct 2.
Abstract
Oxidative maturation of secretory and membrane proteins in the endoplasmic reticulum (ER) is powered by Ero1 oxidases. To prevent cellular hyperoxidation, Ero1 activity can be regulated by intramolecular disulphide switches. Here, we determine the redox-driven shutdown mechanism of Ero1alpha, the housekeeping Ero1 enzyme in human cells. We show that functional silencing of Ero1alpha in cells arises from the formation of a disulphide bond-identified by mass spectrometry--between the active-site Cys(94) (connected to Cys(99) in the active enzyme) and Cys(131). Competition between substrate thiols and Cys(131) creates a feedback loop where activation of Ero1alpha is linked to the availability of its substrate, reduced protein disulphide isomerase (PDI). Overexpression of Ero1alpha-Cys131Ala or the isoform Ero1beta, which does not have an equivalent disulphide switch, leads to augmented ER oxidation. These data reveal a novel regulatory feedback system where PDI emerges as a central regulator of ER redox homoeostasis.
摘要
内质网（ER）中分泌蛋白和膜蛋白的氧化成熟由Ero1氧化酶驱动。为防止细胞过度氧化，Ero1活性可通过分子内二硫键开关进行调节。在此，我们确定了人类细胞中看家Ero1酶Ero1α的氧化还原驱动的关闭机制。我们表明，细胞中Ero1α的功能沉默源于质谱鉴定的活性位点半胱氨酸（Cys）94（与活性酶中的Cys99相连）和Cys131之间形成的二硫键。底物硫醇与Cys131之间的竞争形成了一个反馈回路，其中Ero1α的激活与其底物——还原型蛋白质二硫键异构酶（PDI）的可用性相关联。Ero1α-Cys131Ala或没有等效二硫键开关的异构体Ero1β的过表达导致内质网氧化增强。这些数据揭示了一种新型调节反馈系统，其中PDI成为内质网氧化还原稳态的核心调节因子。
相似文献
1
A novel disulphide switch mechanism in Ero1alpha balances ER oxidation in human cells.Ero1α 中的一种新型二硫键开关机制平衡了人类细胞中的内质网氧化作用。
EMBO J. 2008 Nov 19;27(22):2977-87. doi: 10.1038/emboj.2008.202. Epub 2008 Oct 2.
2
A PDI-catalyzed thiol-disulfide switch regulates the production of hydrogen peroxide by human Ero1.一种由PDI催化的硫醇-二硫键转换调节人Ero1产生过氧化氢的过程。
Free Radic Biol Med. 2015 Jun;83:361-72. doi: 10.1016/j.freeradbiomed.2015.02.011. Epub 2015 Feb 17.
3
Low reduction potential of Ero1alpha regulatory disulphides ensures tight control of substrate oxidation.Ero1α调节性二硫键的低还原电位确保了对底物氧化的严格控制。
EMBO J. 2008 Nov 19;27(22):2988-97. doi: 10.1038/emboj.2008.230. Epub 2008 Oct 30.
4
Different interaction modes for protein-disulfide isomerase (PDI) as an efficient regulator and a specific substrate of endoplasmic reticulum oxidoreductin-1α (Ero1α).不同的蛋白质二硫键异构酶（PDI）相互作用模式作为内质网氧化还原酶 1α（Ero1α）的有效调节剂和特定底物。
J Biol Chem. 2014 Nov 7;289(45):31188-99. doi: 10.1074/jbc.M114.602961. Epub 2014 Sep 25.
5
Disulphide production by Ero1α-PDI relay is rapid and effectively regulated. Ero1α-PDI 接力中二硫键的生成迅速且受到有效调控。
EMBO J. 2010 Oct 6;29(19):3318-29. doi: 10.1038/emboj.2010.203. Epub 2010 Aug 27.
6
Cysteines 208 and 241 in Ero1α are required for maximal catalytic turnover.Ero1α中的半胱氨酸208和241是最大催化周转率所必需的。
Redox Biol. 2016 Apr;7:14-20. doi: 10.1016/j.redox.2015.11.004. Epub 2015 Nov 14.
7
Molecular bases of cyclic and specific disulfide interchange between human ERO1alpha protein and protein-disulfide isomerase (PDI).人 ERO1alpha 蛋白与蛋白二硫键异构酶（PDI）之间的环状和特异性二硫键交换的分子基础。
J Biol Chem. 2011 May 6;286(18):16261-71. doi: 10.1074/jbc.M111.231357. Epub 2011 Mar 11.
8
Human ER Oxidoreductin-1α (Ero1α) Undergoes Dual Regulation through Complementary Redox Interactions with Protein-Disulfide Isomerase.人类内质网氧化还原酶1α（Ero1α）通过与蛋白质二硫键异构酶的互补氧化还原相互作用进行双重调控。
J Biol Chem. 2016 Nov 11;291(46):23952-23964. doi: 10.1074/jbc.M116.735662. Epub 2016 Oct 4.
9
Crystal structures of human Ero1α reveal the mechanisms of regulated and targeted oxidation of PDI.人 Ero1α 的晶体结构揭示了 PDI 受调控和靶向氧化的机制。
EMBO J. 2010 Oct 6;29(19):3330-43. doi: 10.1038/emboj.2010.222. Epub 2010 Sep 10.
10
Biochemical evidence that regulation of Ero1β activity in human cells does not involve the isoform-specific cysteine 262.关于人类细胞中Ero1β活性的调节不涉及同工型特异性半胱氨酸262的生化证据。
Biosci Rep. 2014 Apr 1;34(2). doi: 10.1042/BSR20130124.
引用本文的文献
1
Development of luciferase-based highly sensitive reporters that detect ER-associated protein biogenesis abnormalities.用于检测内质网相关蛋白质生物合成异常的基于荧光素酶的高灵敏度报告基因的开发。
iScience. 2024 Oct 16;27(11):111189. doi: 10.1016/j.isci.2024.111189. eCollection 2024 Nov 15.
2
Enhancing Therapeutic Approaches in Glioblastoma with Pro-Oxidant Treatments and Synergistic Combinations: In Vitro Experience of Doxorubicin and Photodynamic Therapy.通过抗氧化治疗和协同组合增强胶质母细胞瘤的治疗方法：多柔比星和光动力疗法的体外经验。
Int J Mol Sci. 2024 Jul 9;25(14):7525. doi: 10.3390/ijms25147525.
3
Biological mechanisms and clinical significance of endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) in human cancer.内质网氧化还原酶 1 阿尔法（ERO1α）在人类癌症中的生物学机制和临床意义。
J Exp Clin Cancer Res. 2024 Mar 8;43(1):71. doi: 10.1186/s13046-024-02990-4.
4
Biochemical analysis of Komagataella phaffii oxidative folding proposes novel regulatory mechanisms of disulfide bond formation in yeast.毕赤酵母氧化折叠的生化分析提出了酵母中二硫键形成的新调控机制。
Sci Rep. 2023 Aug 31;13(1):14298. doi: 10.1038/s41598-023-41375-z.
5
FAT-switch-based quantitative S-nitrosoproteomics reveals a key role of GSNOR1 in regulating ER functions.基于 FAT 开关的定量 S-亚硝基蛋白质组学揭示了 GSNOR1 在调节内质网功能中的关键作用。
Nat Commun. 2023 Jun 5;14(1):3268. doi: 10.1038/s41467-023-39078-0.
6
A Critical Role for ERO1α in Arterial Thrombosis and Ischemic Stroke.ERO1α 在动脉血栓形成和缺血性中风中的关键作用。
Circ Res. 2023 May 26;132(11):e206-e222. doi: 10.1161/CIRCRESAHA.122.322473. Epub 2023 May 3.
7
Endoplasmic reticulum oxidoreductin provides resilience against reductive stress and hypoxic conditions by mediating luminal redox dynamics.内质网氧化还原酶通过调节腔室内的氧化还原动态，为抵抗还原性应激和低氧条件提供了弹性。
Plant Cell. 2022 Sep 27;34(10):4007-4027. doi: 10.1093/plcell/koac202.
8
The Potential of a Protein Model Synthesized Absent of Methionine.缺乏甲硫氨酸的蛋白质模型的潜力。
Molecules. 2022 Jun 8;27(12):3679. doi: 10.3390/molecules27123679.
9
Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress.将烟酰胺腺嘌呤二核苷酸磷酸生成与内质网蛋白质氧化及应激联系起来的信号通路
Front Mol Biosci. 2022 May 4;9:858142. doi: 10.3389/fmolb.2022.858142. eCollection 2022.
10
Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production.营养素对胰岛β细胞分泌能力和胰岛素生成的调节作用。
Biomolecules. 2022 Feb 20;12(2):335. doi: 10.3390/biom12020335.
本文引用的文献
1
Redox compartmentalization in eukaryotic cells.真核细胞中的氧化还原区室化
Biochim Biophys Acta. 2008 Nov;1780(11):1273-90. doi: 10.1016/j.bbagen.2008.01.011. Epub 2008 Jan 26.
2
Ero1 and redox homeostasis in the endoplasmic reticulum.内质网中的Ero1与氧化还原稳态
Biochim Biophys Acta. 2008 Apr;1783(4):549-56. doi: 10.1016/j.bbamcr.2007.12.011. Epub 2007 Dec 23.
3
The human PDI family: versatility packed into a single fold.人类蛋白质二硫键异构酶家族：集多种功能于单一结构域。
Biochim Biophys Acta. 2008 Apr;1783(4):535-48. doi: 10.1016/j.bbamcr.2007.11.010. Epub 2007 Dec 3.
4
In vivo reduction-oxidation state of protein disulfide isomerase: the two active sites independently occur in the reduced and oxidized forms.蛋白质二硫键异构酶的体内还原-氧化状态：两个活性位点分别以还原态和氧化态存在。
Antioxid Redox Signal. 2008 Jan;10(1):55-64. doi: 10.1089/ars.2007.1837.
5
Modulation of cellular disulfide-bond formation and the ER redox environment by feedback regulation of Ero1.通过Ero1的反馈调节对细胞二硫键形成和内质网氧化还原环境的调控
Cell. 2007 Apr 20;129(2):333-44. doi: 10.1016/j.cell.2007.02.039.
6
Generating disulfides in multicellular organisms: emerging roles for a new flavoprotein family.在多细胞生物中生成二硫键：一个新的黄素蛋白家族的新作用
J Biol Chem. 2007 May 11;282(19):13929-33. doi: 10.1074/jbc.R600037200. Epub 2007 Mar 12.
7
Dynamic retention of Ero1alpha and Ero1beta in the endoplasmic reticulum by interactions with PDI and ERp44.通过与蛋白二硫键异构酶（PDI）和内质网蛋白44（ERp44）相互作用，Ero1α和Ero1β在内质网中的动态保留
Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):274-82. doi: 10.1089/ars.2006.8.274.
8
The multidrug resistance protein 1 (Mrp1), but not Mrp5, mediates export of glutathione and glutathione disulfide from brain astrocytes.多药耐药蛋白1（Mrp1）而非多药耐药蛋白5（Mrp5）介导脑星形胶质细胞中谷胱甘肽和二硫化谷胱甘肽的输出。
J Neurochem. 2006 Apr;97(2):373-84. doi: 10.1111/j.1471-4159.2006.03737.x. Epub 2006 Mar 15.
9
Role of protein disulfide isomerase and other thiol-reactive proteins in HIV-1 envelope protein-mediated fusion.蛋白质二硫键异构酶及其他硫醇反应性蛋白在HIV-1包膜蛋白介导的融合中的作用。
Virology. 2006 Jul 5;350(2):406-17. doi: 10.1016/j.virol.2006.01.041. Epub 2006 Feb 28.
10
Generating disulfides enzymatically: reaction products and electron acceptors of the endoplasmic reticulum thiol oxidase Ero1p.酶促生成二硫键：内质网硫醇氧化酶Ero1p的反应产物和电子受体。
Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):299-304. doi: 10.1073/pnas.0506448103. Epub 2006 Jan 3.
Zotero 插件