Phase separation of protein mixtures is driven by the interplay of homotypic and heterotypic interactions

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

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Fundamental Aspects of Phase-Separated Biomolecular Condensates

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(13), P. 8550 - 8595

Published: June 17, 2024

Biomolecular condensates, formed through phase separation, are upending our understanding in much of molecular, cell, and developmental biology. There is an urgent need to elucidate the physicochemical foundations behaviors properties biomolecular condensates. Here we aim fill this by writing a comprehensive, critical, accessible review on fundamental aspects phase-separated We introduce relevant theoretical background, present basis for computation experimental measurement condensate properties, give mechanistic interpretations terms interactions at molecular residue levels.

Language: Английский

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Coiled-coil domains are sufficient to drive liquid-liquid phase separation in protein models

Biophysical Journal, Journal Year: 2024, Volume and Issue: 123(6), P. 703 - 717

Published: Feb. 15, 2024

Language: Английский

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Disordered regions of condensate-promoting proteins have distinct molecular signatures associated with cellular function

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 168953 - 168953

Published: Jan. 1, 2025

Language: Английский

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Structured protein domains enter the spotlight: modulators of biomolecular condensate form and function

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Disorder-mediated interactions target proteins to specific condensates

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(18), P. 3497 - 3512.e9

Published: Sept. 1, 2024

Language: Английский

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Toward Design Principles for Biomolecular Condensates for Metabolic Pathways

Advanced Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 7, 2025

Abstract Biology uses membrane‐less organelles or biomolecular condensates as dynamic reaction compartments that can form dissolve to regulate biochemical pathways. This has led a flurry of research aiming design new synthetic function crucibles for enzymes and cascades in biotechnology. The mechanisms by which condensate enhance multistep processes including mass action, tuning the chemical environment, scaffolding metabolic channelling is reviewed. These are not inherently beneficial rate enzymatic but also inhibit reaction. Similarly, some aspects likely intrinsically inhibitory retardation diffusion, where net effect will be trade‐off between stimulatory effects. It discussed generalizable conclusions drawn so far how close it principles enzyme microbial cell factories reactions enhanced type suited

Language: Английский

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Universal membranization of synthetic coacervates and biomolecular condensates towards ultrastability and spontaneous emulsification

Nature Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 10, 2025

Language: Английский

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Live-cell quantification reveals viscoelastic regulation of synapsin condensates by α-synuclein

Science Advances, Journal Year: 2025, Volume and Issue: 11(16)

Published: April 18, 2025

Synapsin and α-synuclein represent a growing list of condensate-forming proteins where the material states condensates are directly linked to cellular functions (e.g., neurotransmission) pathology neurodegeneration). However, quantifying condensate properties in living systems has been substantial challenge. Here, we develop micropipette aspiration whole-cell patch-clamp (MAPAC), platform that allows direct quantification live cells. We find 10,000-fold variations viscoelasticity synapsin condensates, regulated by partitioning α-synuclein, marker for synucleinopathies. Through vitro reconstitutions, identify multiple molecular factors distinctly regulate viscosity, interfacial tension, maturation confirming roles α-synuclein. Overall, our study provides unprecedented quantitative insights into neuronal reveals crucial role regulating viscoelasticity. Furthermore, envision MAPAC applicable broad range vivo.

Language: Английский

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Aromatic and arginine content drives multiphasic condensation of protein-RNA mixtures

Biophysical Journal, Journal Year: 2023, Volume and Issue: unknown

Published: July 1, 2023

Multiphasic architectures are found ubiquitously in biomolecular condensates and thought to have important implications for the organization of multiple chemical reactions within same compartment. Many these multiphasic contain RNA addition proteins. Here, we investigate importance different interactions comprising two proteins using computer simulations with a residue-resolution coarse-grained model RNA. We find that multilayered containing both phases, protein-RNA dominate, aromatic residues arginine forming key stabilizing interactions. The total content must be appreciably distinct phases form, show this difference increases as system is driven toward greater multiphasicity. Using trends observed interaction energies system, demonstrate can also construct preferentially concentrated one phase. “rules” identified thus enable design synthetic facilitate further study their function.

Language: Английский

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