生物分子液-液相分离的物理化学机制

doi:10.3866/PKU.WHXB201907053

物理化学学报 >> 2020, Vol. 36 >> Issue (1): 1907053.doi: 10.3866/PKU.WHXB201907053

所属专题：庆祝唐有祺院士百岁华诞专刊

生物分子液-液相分离的物理化学机制

张长胜^1,*(),来鲁华^1,^2,*()

¹ 北京大学化学与分子工程学院，物理化学研究所，分子动态与稳态结构国家重点实验室，北京分子科学国家研究中心，北京 100871
² 北京大学定量生物学中心，北京大学-清华大学生命科学联合中心，北京 100871

收稿日期:2019-07-19 录用日期:2019-09-10 发布日期:2019-09-24
通讯作者: 张长胜,来鲁华 E-mail:changshengzhang@pku.edu.cn;lhlai@pku.edu.cn
作者简介:张长胜副研究员，2005年本科毕业于哈尔滨工业大学理学院，2011年博士毕业于北京大学化学与分子工程学院。2014–2018年在美国得州大学奥斯汀分校做博士后研究。现任北京大学化学学院物理化学研究所副研究员。主要研究方向包括蛋白质相互作用与聚集机理研究、功能蛋白质计算设计、新一代生物分子力场的开发|来鲁华教授，1984年本科毕业于北京大学化学系，1989年获北京大学化学系物理化学博士。现任北京大学化学与分子工程学院物理化学研究所教授。主要研究方向包括基于结构与系统生物学的药物设计方法与应用、蛋白质设计、蛋白质别构及无序蛋白质调控、肿瘤细胞代谢和炎症网络调控机制研究等
基金资助:
国家重点研发计划(2016YFA0502303);国家自然科学基金(21633001)

Physiochemical Mechanisms of Biomolecular Liquid-Liquid Phase Separation

Changsheng Zhang^1,*(),Luhua Lai^1,^2,*()

¹ Beijing National Laboratory for Molecular Science, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Physical Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China
² Center for Quantitative Biology, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, P. R. China

Received:2019-07-19 Accepted:2019-09-10 Published:2019-09-24
Contact: Changsheng Zhang,Luhua Lai E-mail:changshengzhang@pku.edu.cn;lhlai@pku.edu.cn
Supported by:
the National Key Research and Development Program of China(2016YFA0502303);the National Natural Science Foundation of China(21633001)

摘要/Abstract

摘要：

近年来，有关生物分子通过液-液相分离机制进行组织定位、功能调控的研究发展迅速。相分离产生的聚集体在众多细胞活动事件中发挥了关键作用。这些聚集体的生物功能是以相分离的物理化学性质为基础的。本文将从相分离聚集体的基本性质、相图、微观结构，相分离的统计热力学、实验和分子模拟研究等方面阐释相分离物理化学机制研究相关进展。对于生物分子相分离的重要功能体系进行了列举和归纳，收集了相分离研究的模式体系，探讨了生物分子相分离的生物功能同物理化学机制之间的关系，总结了生物分子相分离的调控机制和调控分子的设计方法，并对生物分子相分离物理化学机制研究的未来发展方向进行了展望。

关键词: 生物分子液-液相分离, 液态聚集体, 天然无序蛋白质, 多价作用, 分子聚集的计算模拟, 相分离调控

Abstract:

The discoveries about the functions of biomolecular liquid-liquid phase separation in cell have been increased rapidly in the past decade. Condensates produced by phase separation play key roles in many cellular curial events. These biological functions are based on the physicochemical properties of phase separation. This review discusses the recent progress in understanding the physical and chemical mechanisms of biological liquid-liquid phase separation. (1) We summarized the basic properties and experimental characterization methods of phase separation droplets, including the morphology, fusion, and wetting, along with the dynamic properties of molecules in droplets, which are usually described by diffusion coefficients or viscosity and permeability. (2) We discussed the conditions affecting the liquid-liquid phase separation of biological molecules, including concentration, temperature, ionic strength, pH, and crowding effects. A database for liquid-liquid phase separation, LLPSDB, was introduced, and three types of nucleic acid concentration effects on the phase separation of protein molecules are discussed. These effects depend on the relative interaction strengths of protein-nucleic acid and protein-protein interactions. The major driving force of phase separation is multivalent interactions, and molecular flexibility is necessary for the dynamic properties. We summarized the diverse sources of multivalence, including multiple tandem repetitive domains, regular oligomerization, low-complexity domains (usually intrinsically disordered with repeat motifs for binding), and nucleic acid molecules via the main chain phosphates or repeat sequences. (3) We reviewed the statistical thermodynamics theories for describing the macromolecular liquid-liquid separation, including the Flory-Huggins theory, Overbeek-Voorn correction, random phase approximation method, and field theory simulation method. We discussed the experimental and simulation methods for studying the physiochemical mechanism of liquid-liquid phase separation. Model systems with simplified sequences for experimental studies were listed, including systems for studying the effects of charge properties, residue types, sequence length, and other properties. Molecular simulation methods can provide detailed information regarding the liquid-liquid phase separation process. We introduced two coarse-grain methods, the slab molecular dynamic simulation and Monte Carlo simulation using the lattice model. (4) The physiochemical properties of liquid-liquid phase separation govern the diverse functions of reversible phase transitions in a cell. We collected and analyzed important cases of biomolecular phase separation in cell activities. These biological functions were classified into five categories, including enrichment, sequestration, biological switching cooperation, localization, and mechanical force generation. We linked these functions with the physiochemical properties of liquid-liquid phase separation. To understand the specific phase-separation processes in biological activities, three types of related molecules must be studied: scaffold molecules mainly contributing to aggregate formation, recruited functional client molecules, and molecules that regulate the formation and disassembly of aggregates. We reviewed four regulation methods for the phase separation process, including changing the charge distribution by post-translational modification, changing the molecular concentration by gene expression or degradation regulation, changing the oligomerization state, and changing the cell solution environment (such as pH). Designing compounds for phase separation regulation has attracted significant attention for treating related diseases. Methods for discovering molecules that can regulate post-translational modifications or inhibit interactions in the droplets are emerging. The recently discovered phase separation phenomena and molecules in living organisms represent only the tip of the iceberg. In the future, it will be necessary to systematically examine liquid-liquid phase separation events and related molecules in all phases of biological processes.

Key words: Biomolecular liquid-liquid phase separation, Droplet condensate, Intrinsically disordered protein, Multivalent interaction, Molecular simulation for aggregation, Phase separation regulation

张长胜,来鲁华. 生物分子液-液相分离的物理化学机制[J]. 物理化学学报, 2020, 36(1), 1907053. doi: 10.3866/PKU.WHXB201907053

Changsheng Zhang,Luhua Lai. Physiochemical Mechanisms of Biomolecular Liquid-Liquid Phase Separation[J]. Acta Physico-Chimica Sinica 2020, 36(1), 1907053. doi: 10.3866/PKU.WHXB201907053

链接本文: https://www.whxb.pku.edu.cn/CN/10.3866/PKU.WHXB201907053

https://www.whxb.pku.edu.cn/CN/Y2020/V36/I1/1907053

图/表 5

图1

图2

表1

研究生物分子相分离物理化学机制的模式实验体系"

No.	Description	The objective sequence	Major research results	Ref.
a	RNA molecular with repetitive sequences	47 x CUG，47 x CAG	CAG-repeat RNAs phase-separate in cells. With Mg²⁺ in solution，these two repeat sequence RNA initially phase-separate into liquid-like droplet and then rapidly become cross-linked into gels.	55
b	Nck + N-WASP	The linker L1 of Nck, between the first two SH3 domains	Mutations of L1 significantly affects the occurrence of phase separation. The concentrated distribution of positive charge residues on N-terminal, as well as the weak interactions with the second SH3 domain, are the major driving force for the L1 promoted phase separation.	66
c	(P-X_n-G)_m	With different X and m value	The average hydrophobic index of X can be used to judge whether the protein has lower or upper critical solution temperature. The larger the m value, the stronger the tendency of phase separation. The sequence with upper critical solution temperature can be predicted by the parameters concluded from experiments.	67
d	VRN1 + DNA	The VRN1 linker between the B3 domains	In the model system, the linker was simulated by repetitive Pro-Ser sequences. The introduction of an alkaline residue block and/or an acidic residue block is very important for the morphology of phase separation aggregates.	68
e	PR₃₀ + poly-rA (or poly-rU, poly-rC)	Pro-Arg repetitive sequence with homopolymeric RNA	Condensates formed with pol-rA were more viscous than those formed by poly-rC and poly-rU. The stronger interaction between arginine and adenosine makes poly-rA phase separated droplets have higher density and viscosity. Mixing RNA species generates complex multilayered condensates.	15
f	RP3/SR8 + polyU	RP3/SR8 contain RNA binding motifs RGG/RG/SR	The polyU RNA can modulate the phase behavior of the proteins. When the RNA concentration is lower, increasing the RNA concentration leads to droplet assembly by complex coacervation, and after the RNA concentration reaches to a value, increasing RNA concentration triggers a protein charge inversion, which promotes disassembly.	35
g	polyK + single/double strand nucleic acid	polyK-ss/ds RNA/DNA	PolyK with single strand nucleic acids phase separate into liquid-like droplets, and PolyK with double strand nucleic acids tends to phase separate into gel, apparently because of the difference of charge density. The phase separation morphology is also affected by ionic strength and temperature.	54
h	(PRM)_n + (SH3)_m	Model system for multivalent interaction	The greater the number of repeat domains, the lower the critical concentration of separation phase. The number of repeat domains also affects the tendency of droplet transition to gel state.	42
i	polyE + poly(G-K)	poly(G-K) with different charge patterns	The poly(G-K) protein with more concentrated charge pattern has an increased critical salt concentration for phase separation. Ionic entropy change is the driving force for this phase transition system.	69

表1

表2

细胞活动过程中生物分子相分离的重要作用与机制"

No.	Description	Scaffold molecular; assistant molecules promoting LLPS	The recruited functional client molecules	Regulation of the formation and disassembly of the aggregates	Biological functions	Ref.
a	P granule (fertilized egg cell of elegans)	MEG-3/MEG-4 protein; RNA	Endonuclease (PGL-1 or 3), RNA helicase (GLH, LAF)	Disassemble: phosphorylation by kinase MBK-2/DYRK; assemble: dephosphorylation by phosphatase PP2A	Polarization and asymmetric division of fertilized eggs into somatic and germ cells	2, 83, 84
b	PGL granule (somatic cells of elegans in development)	PGL-1/PGL-3 (RGG domain; RNA, SEPA-1	EPG-2 (promote the solidification of the droplets), Atg8 (initiate autophagic degradation)	Promotion: phosphorylation by kinase mTORC (response to high temperature); inhibition: arginine methylation by EPG11	Autophagic degradation of PGL in somatic cells; response to high temperature	85, 86
c	Synapsin droplets (synapses)	Synapsin 1(C terminal IDP domain)	Synaptic vesicles (DOPE lipid), SH3 domain-containing proteins (such as Grb2)	phosphorylation by kinase CaMKII results in rapidly condensates disassemble and the release of the vesicles	Control the accumulation of synaptic vesicles and their release under stimulations	12, 87
d	Postsynaptic densities	PSD-95 (PSG domain, ligand induced dimerization) + SynGAP (Coiled-coil-PBM domain, trimer)		Disassemble: phosphorylation by kinase SynGAP	Synaptic plasticity in the nervous system, which is the mechanism of long-term potentiation/depression processes	44
e	cGAS foci (HeLa cell)	cGAS (cyclic GMP-AMP synthase N-terminal IDP domain) + dsDNA	The substrate of cGAS: GTP，ATP	Zn²⁺ promotes the phase separation process	dsDNA-induced innate immune signaling	11
f	Stress granule (yeast cell, Hela cell)	Poly-A binding protein (proline-rich domain), Sup35 (prion domain)	mTORC1, DYRK3 N-terminal domain	High temperature or low pH stress drives phase separation; polyA RNA inhibits phase separation; DYRK3 regulates stress granule dissolution ⁸³.	Reversible protective response mechanism under stress.	3, 80, 88
g	Sec body (Drosophila cell, between ER and Golgi apparatus)	Sec16	COPII coated vesicles	Mono-ADP-ribosylation of Sec16 by PARP16 promotes phase separation	Protein secretion inhibition, a protective response mechanism under environmental stress such as starvation	89, 90
h	DNA repair compartment	53BP1	gH2AX + MDC1 (mediator of DNA damage checkpoint protein), tumor suppressor p53		Protect the damaged DNA fragment; recruit repair protein for DNA damage repair	6, 81
i	Nuclear condensate	Nucleoprotein IDP domain, such as BRD4, TAF15 or FUS	genomic loci specifically binding with the scaffold nucleoproteins;		Restructure the genome; physically pulling in targeted genomic loci while pushing out non-targeted regions.	91
j	Heterochromatin foci (in cell nucleus)	HP1α (dimer); DNA	chromatin	Phosphorylated HP1α forms larger and more nuclear puncta; Sgo/LBR promotes/inhibits phase separation	Gene silencing in heterochromatin	92
k	Nuclear speckle (mammalian cells)	Cyclin T1 (histidine-rich domain), DYRK1A (histidine-rich domain)	RNA polymerase Ⅱ C terminal domain, CDK9	CDK7 or TFIIH pre-phosphorylated RNA polymerase Ⅱ promotes phase separation	C-terminal hyper-phosphorylation of RNA polymerase Ⅱ	93, 94
l	Coactivator Puncta	MED1 (intrinsically disordered regions)	RNA polymerase Ⅱ; transcriptional coactivator: BRD4, OCT4, ER		Transcriptional regulation of the enhancer gene, bring two genomic region closer	4, 5
m	Splicing speckle	SRRM1 (Ser/Arg repetitive matrix protein)	Noncoding RNA, splicing factors	Phosphorylation by kinase DYRK3 promotes the condensate dissolution	Pre-mRNA splicing	7
n	Nuclear body (nucleus of Arabidopsis)	FCA+FLL2 (prion like domain)	RNA 3’-ter processing components, polyadenylation proteins: FY, FPA, and FIP1		Reduce transcriptional read-through by promoting proximal polyadenylation at many sites	95
o	Transport granules (neuron cell)	hnRNP A2 (low complexity domain); TDP-43	myelin basic protein mRNA	Phosphorylation by kinase Fyn promotes the condensate dissolution and release mRNA, arginine methylation by PRMT1 inhibits phase separation	Silence the mRNA transcription and transport the mRNA molecules to translation sites	8
p	Nucleolus	GC layer: SURF6 (arginine rich domain) + NPM1 (acidic and basic tracts) ⁹¹; DFC/GC layer: FIB1 (R/G domain)+ NPM1+ RNA ²⁴	DNA/RNA, UBF, Nucleolin		Component synthesis and assembly of ribosomes	25, 96
q	Spindle matrix	BuGZ	α/β tubulin; Aurora A (kinase for spindle apparatus assembly regulation)	Higher temperature promotes the formation of the condensates	Regulation of assembly of the mitotic spindle apparatus	97
r	Pericentriolar material (elegans cell)	SPD-5	α/β tubulin	Assemble: phosphorylation by kinase Polo; disassemble: dephosphorylation by phosphatase PP2A	Facilitate the nucleation and growth of microtubules	98
s	T cell microcluster 1	LAT +Grb2 (SH2 and SH3 domain) + Sos1	Proteins on T cell path way: CD45, ZAP70	Assemble: tyrosine phosphorylation of LAT; disassemble: dephosphorylation by phosphatase PTP1B	Promote the signal output of the T cell signal transduction path way	10
t	T cell microcluster 2	Nephrin + Nck (SH3 domain) + N-WASP (PRM domain)	Arp2/3 complex (nucleate actin filaments)		Promote actin aggregation into filaments	10, 79
u	p62 body	p62 (PB1 and UBA domains) + polyubiquitinated proteins	LC3 (receptor for selective autophagy)	Phosphorylation of p62 by kinase CK2 promotes phase separation	Drives autophagic cargo concentration and segregation	43
v	Cortial body	Sla1 + Ent1 (prion like domain)	Clathrin (adheres to cell membrane and mediates endocytosis)		Actin-independent endocytosis; droplet growth provides a driving force for cell membrane invagination	99

表2

图3

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生物分子液-液相分离的物理化学机制

Physiochemical Mechanisms of Biomolecular Liquid-Liquid Phase Separation

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