用于研究小分子诱导α-突触核蛋白原纤维解聚的位点特异性荧光偏振
Site-Specific Fluorescence Polarization for Studying the Disaggregation of α-Synuclein Fibrils by Small Molecules.
作者信息
Haney Conor M, Cleveland Christina L, Wissner Rebecca F, Owei Lily, Robustelli Jaclyn, Daniels Malcolm J, Canyurt Merve, Rodriguez Priscilla, Ischiropoulos Harry, Baumgart Tobias, Petersson E James
机构信息
Department of Chemistry, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104, United States.
Pharmacology Graduate Group, University of Pennsylvania , 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, United States.
出版信息
Biochemistry. 2017 Feb 7;56(5):683-691. doi: 10.1021/acs.biochem.6b01060. Epub 2016 Nov 11.
Abstract
Fibrillar aggregates of the protein α-synuclein (αS) are one of the hallmarks of Parkinson's disease. Here, we show that measuring the fluorescence polarization (FP) of labels at several sites on αS allows one to monitor changes in the local dynamics of the protein after binding to micelles or vesicles, and during fibril formation. Most significantly, these site-specific FP measurements provide insight into structural remodeling of αS fibrils by small molecules and have the potential for use in moderate-throughput screens to identify small molecules that could be used to treat Parkinson's disease.
摘要
蛋白质α-突触核蛋白（αS）的纤维状聚集体是帕金森病的标志性特征之一。在此，我们表明，测量αS上多个位点标记物的荧光偏振（FP），能够监测该蛋白质与胶束或囊泡结合后以及原纤维形成过程中局部动力学的变化。最为重要的是，这些位点特异性FP测量为小分子对αS原纤维的结构重塑提供了深入了解，并且有潜力用于中等通量筛选，以鉴定可用于治疗帕金森病的小分子。
相似文献
1
Site-Specific Fluorescence Polarization for Studying the Disaggregation of α-Synuclein Fibrils by Small Molecules.用于研究小分子诱导α-突触核蛋白原纤维解聚的位点特异性荧光偏振
Biochemistry. 2017 Feb 7;56(5):683-691. doi: 10.1021/acs.biochem.6b01060. Epub 2016 Nov 11.
2
Direct Visualization of Model Membrane Remodeling by α-Synuclein Fibrillization.通过α-突触核蛋白纤维化对模型膜重塑的直接可视化
Chemphyschem. 2017 Jun 20;18(12):1620-1626. doi: 10.1002/cphc.201700050. Epub 2017 Apr 27.
3
Comparison of α-Synuclein Fibril Inhibition by Four Different Amyloid Inhibitors.四种不同淀粉样蛋白抑制剂对α-突触核蛋白原纤维的抑制作用比较。
ACS Chem Neurosci. 2017 Dec 20;8(12):2722-2733. doi: 10.1021/acschemneuro.7b00261. Epub 2017 Sep 21.
4
Influence of EGCG on α-synuclein (αS) aggregation and identification of their possible binding mode: A computational study using molecular dynamics simulation.EGCG 对 α-突触核蛋白（αS）聚集的影响及其可能结合模式的鉴定：使用分子动力学模拟的计算研究。
Chem Biol Drug Des. 2018 Jan;91(1):162-171. doi: 10.1111/cbdd.13067. Epub 2017 Aug 14.
5
Structural and Aggregation Properties of Alpha-Synuclein Linked to Phospholipase A2 Action.与磷脂酶A2作用相关的α-突触核蛋白的结构和聚集特性
Protein Pept Lett. 2018;25(4):368-378. doi: 10.2174/0929866525666180326120052.
6
Loss in Toxic Function of Aggregates of α -Synuclein Mutants by a β-Synuclein Derived Peptide.β-突触核蛋白衍生肽导致α-突触核蛋白突变体聚集体毒性功能丧失。
Protein Pept Lett. 2017;24(8):757-764. doi: 10.2174/0929866524666170818154033.
7
Transmission electron microscopy characterization of fluorescently labelled amyloid β 1-40 and α-synuclein aggregates.荧光标记的淀粉样蛋白β 1-40 和 α-突触核蛋白聚集体的透射电子显微镜表征。
BMC Biotechnol. 2011 Dec 19;11:125. doi: 10.1186/1472-6750-11-125.
8
Investigation of α-Synuclein Amyloid Fibrils Using the Fluorescent Probe Thioflavin T.采用荧光探针硫黄素 T 研究 α-突触核蛋白淀粉样纤维。
Int J Mol Sci. 2018 Aug 23;19(9):2486. doi: 10.3390/ijms19092486.
9
Suppression, disaggregation, and modulation of γ-Synuclein fibrillation pathway by green tea polyphenol EGCG.通过绿茶多酚 EGCG 抑制、解聚和调节 γ-突触核蛋白纤维形成途径。
Protein Sci. 2019 Feb;28(2):382-402. doi: 10.1002/pro.3549. Epub 2018 Dec 20.
10
Critical nucleus of Greek-key-like core of α-synuclein protofibril and its disruption by dopamine and norepinephrine.α-突触核蛋白原纤维中希腊钥匙样核心的关键核及其被多巴胺和去甲肾上腺素破坏。
Phys Chem Chem Phys. 2019 Dec 18;22(1):203-211. doi: 10.1039/c9cp04610k.
引用本文的文献
1
Multivalency drives interactions of alpha-synuclein fibrils with tau.多价性驱动α-突触核蛋白纤维与 tau 的相互作用。
PLoS One. 2024 Sep 10;19(9):e0309416. doi: 10.1371/journal.pone.0309416. eCollection 2024.
2
The Effects of Lipids on α-Synuclein Aggregation In Vitro.脂质对α-突触核蛋白体外聚集的影响。
Biomolecules. 2023 Oct 2;13(10):1476. doi: 10.3390/biom13101476.
3
Semi-Synthetic CoA-α-Synuclein Constructs Trap N-Terminal Acetyltransferase NatB for Binding Mechanism Studies.半合成 CoA-α-突触核蛋白构建体捕获 N 端乙酰转移酶 NatB 用于结合机制研究。
J Am Chem Soc. 2023 Jun 28;145(25):14019-14030. doi: 10.1021/jacs.3c03887. Epub 2023 Jun 15.
4
FRETing about the details: Case studies in the use of a genetically encoded fluorescent amino acid for distance-dependent energy transfer.FRET 技术：利用基因编码荧光氨基酸进行距离依赖能量转移的案例研究。
Protein Sci. 2023 May;32(5):e4633. doi: 10.1002/pro.4633.
5
Effects of Mutations and Post-Translational Modifications on α-Synuclein In Vitro Aggregation.突变和翻译后修饰对α-突触核蛋白体外聚集的影响。
J Mol Biol. 2022 Dec 15;434(23):167859. doi: 10.1016/j.jmb.2022.167859. Epub 2022 Oct 19.
6
Deciphering the Structure and Formation of Amyloids in Neurodegenerative Diseases With Chemical Biology Tools.利用化学生物学工具解析神经退行性疾病中淀粉样蛋白的结构与形成
Front Chem. 2022 May 12;10:886382. doi: 10.3389/fchem.2022.886382. eCollection 2022.
7
Cysteine-Based Mimic of Arginylation Reproduces Neuroprotective Effects of the Authentic Post-Translational Modification on α-Synuclein.半胱氨酸模拟精氨酸化再现了真实的翻译后修饰对α-突触核蛋白的神经保护作用。
J Am Chem Soc. 2022 May 4;144(17):7911-7918. doi: 10.1021/jacs.2c02499. Epub 2022 Apr 22.
8
Genetic encoding of a highly photostable, long lifetime fluorescent amino acid for imaging in mammalian cells.用于哺乳动物细胞成像的一种高光稳定性、长寿命荧光氨基酸的遗传编码。
Chem Sci. 2021 Aug 3;12(36):11955-11964. doi: 10.1039/d1sc01914g. eCollection 2021 Sep 22.
9
Green Tea Polyphenol Epigallocatechin-Gallate in Amyloid Aggregation and Neurodegenerative Diseases.绿茶多酚表没食子儿没食子酸酯在淀粉样蛋白聚集和神经退行性疾病中的作用
Front Neurosci. 2021 Sep 14;15:718188. doi: 10.3389/fnins.2021.718188. eCollection 2021.
10
Quantitative interrogation of protein co-aggregation using multi-color fluorogenic protein aggregation sensors.使用多色荧光蛋白聚集传感器对蛋白质共聚集进行定量分析。
Chem Sci. 2021 May 20;12(24):8468-8476. doi: 10.1039/d1sc01122g.
本文引用的文献
1
Toxic Dopamine Metabolite DOPAL Forms an Unexpected Dicatechol Pyrrole Adduct with Lysines of α-Synuclein.毒性多巴胺代谢物 DOPAL 与α-突触核蛋白的赖氨酸形成意想不到的二酚吡咯加合物。
Angew Chem Int Ed Engl. 2016 Jun 20;55(26):7374-8. doi: 10.1002/anie.201600277. Epub 2016 May 9.
2
Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein.全长人α-突触核蛋白致病原纤维的固态核磁共振结构
Nat Struct Mol Biol. 2016 May;23(5):409-15. doi: 10.1038/nsmb.3194. Epub 2016 Mar 28.
3
Structural disorder of monomeric α-synuclein persists in mammalian cells.单体α-突触核蛋白的结构无序在哺乳动物细胞中持续存在。
Nature. 2016 Feb 4;530(7588):45-50. doi: 10.1038/nature16531. Epub 2016 Jan 25.
4
Comparison of strategies for non-perturbing labeling of α-synuclein to study amyloidogenesis.用于研究淀粉样蛋白生成的α-突触核蛋白非扰动性标记策略的比较。
Org Biomol Chem. 2016 Feb 7;14(5):1584-92. doi: 10.1039/c5ob02329g.
5
Ring substitution influences oxidative cyclisation and reactive metabolite formation of nordihydroguaiaretic acid analogues.环取代影响去甲二氢愈创木酸类似物的氧化环化和活性代谢物形成。
Bioorg Med Chem. 2015 Nov 1;23(21):7007-14. doi: 10.1016/j.bmc.2015.09.039. Epub 2015 Sep 25.
6
Oligomerization and Membrane-binding Properties of Covalent Adducts Formed by the Interaction of α-Synuclein with the Toxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL).α-突触核蛋白与有毒多巴胺代谢物3,4-二羟基苯乙醛（DOPAL）相互作用形成的共价加合物的寡聚化及膜结合特性
J Biol Chem. 2015 Nov 13;290(46):27660-79. doi: 10.1074/jbc.M115.686584. Epub 2015 Sep 17.
7
Structure of the toxic core of α-synuclein from invisible crystals.来自不可见晶体的α-突触核蛋白毒性核心结构。
Nature. 2015 Sep 24;525(7570):486-90. doi: 10.1038/nature15368. Epub 2015 Sep 9.
8
New insights into cellular α-synuclein homeostasis in health and disease.健康与疾病中细胞α-突触核蛋白稳态的新见解。
Curr Opin Neurobiol. 2016 Feb;36:15-22. doi: 10.1016/j.conb.2015.07.007. Epub 2015 Aug 15.
9
KTKEGV repeat motifs are key mediators of normal α-synuclein tetramerization: Their mutation causes excess monomers and neurotoxicity.KTKEGV重复基序是正常α-突触核蛋白四聚化的关键介质：它们的突变会导致过量的单体和神经毒性。
Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9596-601. doi: 10.1073/pnas.1505953112. Epub 2015 Jul 7.
10
Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation.导致帕金森病的α-突触核蛋白错义突变将天然四聚体转变为单体，作为疾病起始的一种机制。
Nat Commun. 2015 Jun 16;6:7314. doi: 10.1038/ncomms8314.
Zotero 插件