Polyphasic linkage and the impact of ligand binding on the regulation of biomolecular condensates DOI Creative Commons
Kiersten M. Ruff, Furqan Dar, Rohit V. Pappu

et al.

Biophysics Reviews, Journal Year: 2021, Volume and Issue: 2(2)

Published: June 1, 2021

Cellular matter can be spatially and temporally organized into membraneless biomolecular condensates. The current thinking is that these condensates form dissolve via phase transitions driven by one or more condensate-specific multivalent macromolecules known as scaffolds. Cells likely regulate condensate formation dissolution exerting control over the concentrations of regulatory molecules, which we refer to ligands. Wyman Gill introduced framework polyphasic linkage explain how ligands exert thermodynamic transitions. This review focuses on describing concepts relevance such a mechanism for controlling dissolution. We describe ligand-mediated scaffold behavior quantified experimentally. Further, build recent studies highlight features make them suppressors vs drivers separation. Finally, areas where advances are needed further understand in complex cellular environments. These include understanding effects networks modulate controlled different combinations homotypic heterotypic interactions among macromolecules. Insights gained from application should useful designing novel pharmaceutical

Language: Английский

A conceptual framework for understanding phase separation and addressing open questions and challenges DOI Creative Commons
Tanja Mittag, Rohit V. Pappu

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(12), P. 2201 - 2214

Published: June 1, 2022

Language: Английский

Citations

493
The molecular basis for cellular function of intrinsically disordered protein regions DOI
Alex S. Holehouse, Birthe B. Kragelund

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 187 - 211

Published: Nov. 13, 2023

Language: Английский

Citations

235
Modulating biomolecular condensates: a novel approach to drug discovery DOI Creative Commons
Diana M. Mitrea, Matthäus Mittasch, Beatriz Ferreira Gomes

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(11), P. 841 - 862

Published: Aug. 16, 2022

In the past decade, membraneless assemblies known as biomolecular condensates have been reported to play key roles in many cellular functions by compartmentalizing specific proteins and nucleic acids subcellular environments with distinct properties. Furthermore, growing evidence supports view that often form phase separation, which a single-phase system demixes into two-phase consisting of condensed dilute particular biomolecules. Emerging understanding condensate function normal aberrant states, mechanisms formation, is providing new insights human disease revealing novel therapeutic opportunities. this Perspective, we propose such could enable previously unexplored drug discovery approach based on identifying condensate-modifying therapeutics (c-mods), discuss strategies, techniques challenges involved.

Language: Английский

Citations

232
Phase Transitions of Associative Biomacromolecules DOI
Rohit V. Pappu, Samuel R. Cohen, Furqan Dar

et al.

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(14), P. 8945 - 8987

Published: March 7, 2023

Multivalent proteins and nucleic acids, collectively referred to as multivalent associative biomacromolecules, provide the driving forces for formation compositional regulation of biomolecular condensates. Here, we review key concepts phase transitions aqueous solutions specifically that include folded domains intrinsically disordered regions. The these systems come under rubric coupled segregative transitions. underlying processes are presented, their relevance condensates is discussed.

Language: Английский

Citations

229
Sequence-encoded and composition-dependent protein-RNA interactions control multiphasic condensate morphologies DOI Creative Commons
Taranpreet Kaur, Muralikrishna Raju, Ibraheem Alshareedah

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Feb. 8, 2021

Multivalent protein-protein and protein-RNA interactions are the drivers of biological phase separation. Biomolecular condensates typically contain a dense network multiple proteins RNAs, their competing molecular play key roles in regulating condensate composition structure. Employing ternary system comprising prion-like polypeptide (PLP), arginine-rich (RRP), RNA, we show that competition between PLP RNA for single shared partner, RRP, leads to RNA-induced demixing PLP-RRP into stable coexisting phases-homotypic heterotypic RRP-RNA condensates. The morphology these biphasic (non-engulfing/ partial engulfing/ complete engulfing) is determined by RNA-to-RRP stoichiometry hierarchy intermolecular interactions, providing glimpse broad range multiphasic patterns accessible Our findings provide minimal set physical rules govern spatial organization multicomponent biomolecular

Language: Английский

Citations

212
Phase-separating RNA-binding proteins form heterogeneous distributions of clusters in subsaturated solutions DOI Creative Commons
Mrityunjoy Kar,

Furqan Dar,

Timothy J. Welsh

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(28)

Published: July 5, 2022

Macromolecular phase separation is thought to be one of the processes that drives formation membraneless biomolecular condensates in cells. The dynamics are follow tenets classical nucleation theory, and, therefore, subsaturated solutions should devoid clusters with more than a few molecules. We tested this prediction using vitro biophysical studies characterize phase-separating RNA-binding proteins intrinsically disordered prion-like domains and domains. Surprisingly, direct contradiction expectations from we find characterized by presence heterogeneous distributions clusters. cluster sizes, which dominated small species, shift continuously toward larger sizes as protein concentrations increase approach saturation concentration. As result, many encompass tens hundreds molecules, while less 1% mesoscale species several hundred nanometers diameter. supersaturated strongly coupled via sequence-encoded interactions. also can decoupled solutes well specific sets mutations. Our findings, concordant predictions for associative polymers, implicate an interplay between networks sequence-specific solubility-determining interactions that, respectively, govern above occurs.

Language: Английский

Citations

208
Liquid-liquid phase separation: Orchestrating cell signaling through time and space DOI Creative Commons
Qi Su, Sohum Mehta, Jin Zhang

et al.

Molecular Cell, Journal Year: 2021, Volume and Issue: 81(20), P. 4137 - 4146

Published: Oct. 1, 2021

Language: Английский

Citations

140
Membrane surfaces regulate assembly of ribonucleoprotein condensates DOI
Wilton T. Snead, Ameya P. Jalihal, Therese M. Gerbich

et al.

Nature Cell Biology, Journal Year: 2022, Volume and Issue: 24(4), P. 461 - 470

Published: April 1, 2022

Language: Английский

Citations

124
Learning the chemical grammar of biomolecular condensates DOI
Henry R. Kilgore,

Richard A. Young

Nature Chemical Biology, Journal Year: 2022, Volume and Issue: 18(12), P. 1298 - 1306

Published: June 27, 2022

Language: Английский

Citations

116
Phase separation of protein mixtures is driven by the interplay of homotypic and heterotypic interactions DOI Creative Commons
Mina Farag, Wade M. Borcherds, Anne Bremer

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 8, 2023

Prion-like low-complexity domains (PLCDs) are involved in the formation and regulation of distinct biomolecular condensates that form via phase separation coupled to percolation. Intracellular often encompass numerous proteins with PLCDs. Here, we combine simulations experiments study mixtures PLCDs from two RNA-binding proteins, hnRNPA1 FUS. Using experiments, find 1:1 A1-LCD FUS-LCD undergo more readily than either on their own due complementary electrostatic interactions. Tie line analysis reveals stoichiometric ratios different components sequence-encoded interactions contribute jointly driving forces for condensate formation. Simulations also show spatial organization within is governed by relative strengths homotypic versus heterotypic We uncover rules how interaction sequence lengths modulate conformational preferences molecules at interfaces formed proteins.

Language: Английский

Citations

96