芳香族残基的价态和模式决定了类朊样结构域的相行为。
Valence and patterning of aromatic residues determine the phase behavior of prion-like domains.
机构信息
Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.
出版信息
Science. 2020 Feb 7;367(6478):694-699. doi: 10.1126/science.aaw8653.
Abstract
Prion-like domains (PLDs) can drive liquid-liquid phase separation (LLPS) in cells. Using an integrative biophysical approach that includes nuclear magnetic resonance spectroscopy, small-angle x-ray scattering, and multiscale simulations, we have uncovered sequence features that determine the overall phase behavior of PLDs. We show that the numbers (valence) of aromatic residues in PLDs determine the extent of temperature-dependent compaction of individual molecules in dilute solutions. The valence of aromatic residues also determines full binodals that quantify concentrations of PLDs within coexisting dilute and dense phases as a function of temperature. We also show that uniform patterning of aromatic residues is a sequence feature that promotes LLPS while inhibiting aggregation. Our findings lead to the development of a numerical stickers-and-spacers model that enables predictions of full binodals of PLDs from their sequences.
摘要
类朊病毒结构域 (PLD) 可在细胞中驱动液-液相分离 (LLPS)。我们采用了一种综合的生物物理方法，包括核磁共振波谱、小角 X 射线散射和多尺度模拟，揭示了决定 PLD 整体相行为的序列特征。我们表明，PLD 中芳香族残基的数量（价数）决定了单个分子在稀溶液中随温度变化的致密程度。芳香族残基的价数还决定了全双折射，全双折射定量地表示了共存的稀相和密相中的 PLD 浓度随温度的变化。我们还表明，芳香族残基的均匀图案化是促进 LLPS 同时抑制聚集的序列特征。我们的发现导致了一种数值贴纸和间隔物模型的发展，该模型能够从 PLD 的序列预测其全双折射。
相似文献
1
Valence and patterning of aromatic residues determine the phase behavior of prion-like domains.芳香族残基的价态和模式决定了类朊样结构域的相行为。
Science. 2020 Feb 7;367(6478):694-699. doi: 10.1126/science.aaw8653.
2
Deciphering how naturally occurring sequence features impact the phase behaviours of disordered prion-like domains.解析天然序列特征如何影响无规则朊病毒样结构域的相行为。
Nat Chem. 2022 Feb;14(2):196-207. doi: 10.1038/s41557-021-00840-w. Epub 2021 Dec 20.
3
Interplay of folded domains and the disordered low-complexity domain in mediating hnRNPA1 phase separation.折叠结构域和无序低复杂度结构域在介导 hnRNPA1 相分离中的相互作用。
Nucleic Acids Res. 2021 Mar 18;49(5):2931-2945. doi: 10.1093/nar/gkab063.
4
A Molecular Grammar Governing the Driving Forces for Phase Separation of Prion-like RNA Binding Proteins.一种分子语法，用于控制朊病毒样 RNA 结合蛋白相分离的驱动力。
Cell. 2018 Jul 26;174(3):688-699.e16. doi: 10.1016/j.cell.2018.06.006. Epub 2018 Jun 28.
5
Electrostatic modulation of hnRNPA1 low-complexity domain liquid-liquid phase separation and aggregation.hnRNPA1 低复杂度结构域液-液相分离和聚集的静电调控。
Protein Sci. 2021 Jul;30(7):1408-1417. doi: 10.1002/pro.4108. Epub 2021 May 22.
6
Phase separation in amino acid mixtures is governed by composition.氨基酸混合物的相分离受组成控制。
Biophys J. 2022 Nov 1;121(21):4119-4127. doi: 10.1016/j.bpj.2022.09.031. Epub 2022 Sep 29.
7
A multi-step nucleation process determines the kinetics of prion-like domain phase separation.多步成核过程决定了类朊病毒结构域相分离的动力学。
Nat Commun. 2021 Jul 23;12(1):4513. doi: 10.1038/s41467-021-24727-z.
8
Phase Separation of Heterogeneous Nuclear Ribonucleoprotein A1 upon Specific RNA-Binding Observed by Magnetic Resonance.磁共振观察到特异性 RNA 结合导致异质核核糖核蛋白 A1 的液-液相分离
Angew Chem Int Ed Engl. 2022 Oct 4;61(40):e202204311. doi: 10.1002/anie.202204311. Epub 2022 Aug 31.
9
TAR DNA-binding protein 43 (TDP-43) liquid-liquid phase separation is mediated by just a few aromatic residues.TAR DNA 结合蛋白 43（TDP-43）的液-液相分离仅由几个芳香族残基介导。
J Biol Chem. 2018 Apr 20;293(16):6090-6098. doi: 10.1074/jbc.AC117.001037. Epub 2018 Mar 6.
10
A Prion-like Domain in Transcription Factor EBF1 Promotes Phase Separation and Enables B Cell Programming of Progenitor Chromatin.转录因子 EBF1 中的类朊病毒结构域促进液-液相分离，并使祖细胞染色质具有 B 细胞编程能力。
Immunity. 2020 Dec 15;53(6):1151-1167.e6. doi: 10.1016/j.immuni.2020.10.009. Epub 2020 Nov 6.
引用本文的文献
1
A label-free method for measuring the composition of multicomponent biomolecular condensates.一种用于测量多组分生物分子凝聚物组成的无标记方法。
Nat Chem. 2025 Sep 3. doi: 10.1038/s41557-025-01928-3.
2
Epsin1 enforces a condensation-dependent checkpoint for ubiquitylated cargo during clathrin-mediated endocytosis.Epsin1在网格蛋白介导的内吞作用过程中，对泛素化货物执行依赖于凝聚的检查点功能。
Nat Commun. 2025 Aug 25;16(1):7929. doi: 10.1038/s41467-025-63238-z.
3
Biomolecular phase separation in tumorigenesis: from aberrant condensates to therapeutic vulnerabilities.肿瘤发生中的生物分子相分离：从异常凝聚物到治疗靶点
Mol Cancer. 2025 Aug 23;24(1):220. doi: 10.1186/s12943-025-02428-1.
4
Promiscuous and multivalent interactions between Eps15 and partner protein Dab2 generate a complex interaction network.Eps15与伴侣蛋白Dab2之间杂乱且多价的相互作用产生了一个复杂的相互作用网络。
Nat Commun. 2025 Aug 21;16(1):7783. doi: 10.1038/s41467-025-63090-1.
5
Current practices in the study of biomolecular condensates: a community comment.生物分子凝聚物研究的当前实践：一份群体评论。
Nat Commun. 2025 Aug 19;16(1):7730. doi: 10.1038/s41467-025-62055-8.
6
YAP charge patterning mediates signal integration through transcriptional co-condensates.YAP电荷模式通过转录共凝聚物介导信号整合。
Nat Commun. 2025 Aug 12;16(1):7454. doi: 10.1038/s41467-025-62157-3.
7
Cooperation and competition of basepairing and electrostatic interactions in mixtures of DNA nanostars and polylysine.DNA纳米星与聚赖氨酸混合物中碱基配对和静电相互作用的协同与竞争
ArXiv. 2025 Jul 22:arXiv:2507.16179v1.
8
The Transcription Machinery and the Driving Force of the Transcriptional Molecular Condensate: The Role of Phosphates.转录机制与转录分子凝聚物的驱动力：磷酸盐的作用
Curr Issues Mol Biol. 2025 Jul 20;47(7):571. doi: 10.3390/cimb47070571.
9
Structural and Functional Relevance of Charge-Based Transient Interactions inside Intrinsically Disordered Proteins.内在无序蛋白质内部基于电荷的瞬态相互作用的结构与功能相关性
ACS Phys Chem Au. 2025 Apr 15;5(4):356-366. doi: 10.1021/acsphyschemau.5c00005. eCollection 2025 Jul 23.
10
Functions of Intrinsically Disordered Regions.内在无序区域的功能。
Biology (Basel). 2025 Jul 4;14(7):810. doi: 10.3390/biology14070810.
本文引用的文献
1
First-generation predictors of biological protein phase separation.生物蛋白质相分离的第一代预测因子。
Curr Opin Struct Biol. 2019 Oct;58:88-96. doi: 10.1016/j.sbi.2019.05.016. Epub 2019 Jun 25.
2
Structural basis for reversible amyloids of hnRNPA1 elucidates their role in stress granule assembly.hnRNPA1 可逆淀粉样纤维的结构基础阐明了其在应激颗粒组装中的作用。
Nat Commun. 2019 May 1;10(1):2006. doi: 10.1038/s41467-019-09902-7.
3
Phase Separation of Intrinsically Disordered Proteins.内在无序蛋白质的相分离
Methods Enzymol. 2018;611:1-30. doi: 10.1016/bs.mie.2018.09.035. Epub 2018 Oct 31.
4
Conformational preferences and phase behavior of intrinsically disordered low complexity sequences: insights from multiscale simulations.无规卷曲低复杂度序列的构象偏好和相行为：多尺度模拟的见解。
Curr Opin Struct Biol. 2019 Jun;56:1-10. doi: 10.1016/j.sbi.2018.10.003. Epub 2018 Nov 12.
5
Relation between single-molecule properties and phase behavior of intrinsically disordered proteins.无规卷曲蛋白的单分子特性与相行为之间的关系。
Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):9929-9934. doi: 10.1073/pnas.1804177115. Epub 2018 Sep 14.
6
A Molecular Grammar Governing the Driving Forces for Phase Separation of Prion-like RNA Binding Proteins.一种分子语法，用于控制朊病毒样 RNA 结合蛋白相分离的驱动力。
Cell. 2018 Jul 26;174(3):688-699.e16. doi: 10.1016/j.cell.2018.06.006. Epub 2018 Jun 28.
7
Atomic structures of FUS LC domain segments reveal bases for reversible amyloid fibril formation.FUS LC 结构域片段的原子结构揭示了其可逆淀粉样纤维形成的基础。
Nat Struct Mol Biol. 2018 Apr;25(4):341-346. doi: 10.1038/s41594-018-0050-8. Epub 2018 Apr 2.
8
Atomic structures of low-complexity protein segments reveal kinked β sheets that assemble networks.低复杂性蛋白质片段的原子结构揭示了组装网络的扭结β折叠。
Science. 2018 Feb 9;359(6376):698-701. doi: 10.1126/science.aan6398.
9
Collapse Transitions of Proteins and the Interplay Among Backbone, Sidechain, and Solvent Interactions.蛋白质的折叠转变以及主链、侧链和溶剂相互作用之间的相互影响。
Annu Rev Biophys. 2018 May 20;47:19-39. doi: 10.1146/annurev-biophys-070317-032838. Epub 2018 Jan 18.
10
Phase separation of a yeast prion protein promotes cellular fitness.酵母朊病毒蛋白的液-液相分离促进细胞适应度。
Science. 2018 Jan 5;359(6371). doi: 10.1126/science.aao5654.
Zotero 插件