Impact of Macromolecular Crowding and Compression on Protein–Protein Interactions and Liquid–Liquid Phase Separation Phenomena

2019 ◽  
Vol 52 (4) ◽  
pp. 1772-1784 ◽  
Author(s):  
Karin Julius ◽  
Jonathan Weine ◽  
Mimi Gao ◽  
Jan Latarius ◽  
Mirko Elbers ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Protein Interactions ◽  
Macromolecular Crowding ◽  
Liquid Phase Separation ◽  
Protein Protein Interactions ◽  
Liquid Liquid Phase Separation

scholarly journals Bi-directional protein-protein interactions control liquid-liquid phase separation of PSD-95 and its interaction partners

2021 ◽  
Author(s):  
Nikolaj Riis Christensen ◽  
Christian Parsbæk Pedersen ◽  
Vita Sereikaite ◽  
Jannik Nedergaard Pedersen ◽  
Maria Vistrup-Parry ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Protein Interactions ◽  
Postsynaptic Density ◽  
Specific Protein ◽  
Liquid Phase Separation ◽  
Protein Protein Interactions ◽  
New Perspective ◽  
Liquid Liquid Phase Separation

SUMMARYThe organization of the postsynaptic density (PSD), a protein-dense semi-membraneless organelle, is mediated by numerous specific protein-protein interactions (PPIs) which constitute a functional post-synapse. Postsynaptic density protein 95 (PSD-95) interacts with a manifold of proteins, including the C-terminal of transmembrane AMPA receptor (AMAPR) regulatory proteins (TARPs). Here, we uncover the minimal essential peptide responsible for the stargazin (TARP-γ2) mediated liquid-liquid phase separation (LLPS) formation of PSD-95 and other key protein constituents of the PSD. Furthermore, we find that pharmacological inhibitors of PSD-95 can facilitate formation of LLPS. We found that in some cases LLPS formation is dependent on multivalent interactions while in other cases short peptides carrying a high charge are sufficient to promote LLPS in complex systems. This study offers a new perspective on PSD-95 interactions and their role in LLPS formation, while also considering the role of affinity over multivalency in LLPS systems.

scholarly journals Expansion of Intrinsically Disordered Proteins Increases the Range of Stability of Liquid–Liquid Phase Separation

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4705
Author(s):  
Adiran Garaizar ◽  
Ignacio Sanchez-Burgos ◽  
Rosana Collepardo-Guevara ◽  
Jorge R. Espinosa
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Protein Interactions ◽  
Conformational Dynamics ◽  
Liquid Phase Separation ◽  
Phase Behaviour ◽  
Coarse Grained ◽  
Protein Protein Interactions ◽  
Intrinsically Disordered ◽  
Liquid Liquid Phase Separation

Proteins containing intrinsically disordered regions (IDRs) are ubiquitous within biomolecular condensates, which are liquid-like compartments within cells formed through liquid–liquid phase separation (LLPS). The sequence of amino acids of a protein encodes its phase behaviour, not only by establishing the patterning and chemical nature (e.g., hydrophobic, polar, charged) of the various binding sites that facilitate multivalent interactions, but also by dictating the protein conformational dynamics. Besides behaving as random coils, IDRs can exhibit a wide-range of structural behaviours, including conformational switching, where they transition between alternate conformational ensembles. Using Molecular Dynamics simulations of a minimal coarse-grained model for IDRs, we show that the role of protein conformation has a non-trivial effect in the liquid–liquid phase behaviour of IDRs. When an IDR transitions to a conformational ensemble enriched in disordered extended states, LLPS is enhanced. In contrast, IDRs that switch to ensembles that preferentially sample more compact and structured states show inhibited LLPS. This occurs because extended and disordered protein conformations facilitate LLPS-stabilising multivalent protein–protein interactions by reducing steric hindrance; thereby, such conformations maximize the molecular connectivity of the condensed liquid network. Extended protein configurations promote phase separation regardless of whether LLPS is driven by homotypic and/or heterotypic protein–protein interactions. This study sheds light on the link between the dynamic conformational plasticity of IDRs and their liquid–liquid phase behaviour.

scholarly journals Bi-Directional Protein-Protein Interactions Control Liquid-Liquid Phase Separation of PSD-95 and Its Interaction Partners

2021 ◽  
Author(s):  
Nikolaj Riis Christensen ◽  
Christian Parsbæk Pedersen ◽  
Vita Sereikaite ◽  
Jannik Nedergaard Pedersen ◽  
Maria Vistrup-Parry ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Protein Interactions ◽  
Liquid Phase Separation ◽  
Protein Protein Interactions ◽  
Interaction Partners ◽  
Liquid Liquid Phase Separation

scholarly journals Liquid–Liquid Phase Separation in Crowded Environments

2020 ◽  
Vol 21 (16) ◽  
pp. 5908 ◽  
Author(s):  
Alain A. M. André ◽  
Evan Spruijt
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Macromolecular Crowding ◽  
Liquid Phase Separation ◽  
The Impact ◽  
Crowded Environments ◽  
Liquid Liquid Phase Separation ◽  
In Cells

Biomolecular condensates play a key role in organizing cellular fluids such as the cytoplasm and nucleoplasm. Most of these non-membranous organelles show liquid-like properties both in cells and when studied in vitro through liquid–liquid phase separation (LLPS) of purified proteins. In general, LLPS of proteins is known to be sensitive to variations in pH, temperature and ionic strength, but the role of crowding remains underappreciated. Several decades of research have shown that macromolecular crowding can have profound effects on protein interactions, folding and aggregation, and it must, by extension, also impact LLPS. However, the precise role of crowding in LLPS is far from trivial, as most condensate components have a disordered nature and exhibit multiple weak attractive interactions. Here, we discuss which factors determine the scope of LLPS in crowded environments, and we review the evidence for the impact of macromolecular crowding on phase boundaries, partitioning behavior and condensate properties. Based on a comparison of both in vivo and in vitro LLPS studies, we propose that phase separation in cells does not solely rely on attractive interactions, but shows important similarities to segregative phase separation.

Reentrant condensation, liquid–liquid phase separation and crystallization in protein solutions induced by multivalent metal ions

2014 ◽  
Vol 86 (2) ◽  
pp. 191-202 ◽  
Author(s):  
Fajun Zhang ◽  
Felix Roosen-Runge ◽  
Andrea Sauter ◽  
Marcell Wolf ◽  
Robert M. J. Jacobs ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Metal Ions ◽  
Protein Interactions ◽  
Protein Crystallization ◽  
Liquid Phase Separation ◽  
Protein Solutions ◽  
Metastable Liquid ◽  
Multivalent Metal ◽  
Liquid Liquid Phase Separation

Abstract We briefly summarize the recent progress in tuning protein interactions as well as phase behavior in protein solutions using multivalent metal ions. We focus on the influence of control parameters and the mechanism of reentrant condensation, the metastable liquid–liquid phase separation and classical vs. non-classical pathways of protein crystallization.

scholarly journals Liquid–Liquid Phase Separation in the Presence of Macromolecular Crowding and State-Dependent Kinetics

2021 ◽  
Vol 22 (13) ◽  
pp. 6675
Author(s):  
Alick-O. Vweza ◽  
Chul-Gyu Song ◽  
Kil-To Chong
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Late Stage ◽  
Macromolecular Crowding ◽  
Liquid Phase Separation ◽  
Self Organization ◽  
State Dependent ◽  
Liquid Liquid Phase Separation

Biomolecular condensates formed via liquid–liquid phase separation (LLPS) are increasingly being shown to play major roles in cellular self-organization dynamics in health and disease. It is well established that macromolecular crowding has a profound impact on protein interactions, particularly those that lead to LLPS. Although synthetic crowding agents are used during in vitro LLPS experiments, they are considerably different from the highly crowded nucleo-/cytoplasm and the effects of in vivo crowding remain poorly understood. In this work, we applied computational modeling to investigate the effects of macromolecular crowding on LLPS. To include biologically relevant LLPS dynamics, we extended the conventional Cahn–Hilliard model for phase separation by coupling it to experimentally derived macromolecular crowding dynamics and state-dependent reaction kinetics. Through extensive field-theoretic computer simulations, we show that the inclusion of macromolecular crowding results in late-stage coarsening and the stabilization of relatively smaller condensates. At a high crowding concentration, there is an accelerated growth and late-stage arrest of droplet formation, effectively resulting in anomalous labyrinthine morphologies akin to protein gelation observed in experiments. These results not only elucidate the crowder effects observed in experiments, but also highlight the importance of including state-dependent kinetics in LLPS models, and may help in designing further experiments to probe the intricate roles played by LLPS in self-organization dynamics of cells.

scholarly journals Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau

2021 ◽  
Vol 433 (2) ◽  
pp. 166731
Author(s):  
Yanxian Lin ◽  
Yann Fichou ◽  
Andrew P. Longhini ◽  
Luana C. Llanes ◽  
Pengyi Yin ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Hydrophobic Interaction ◽  
Liquid Phase Separation ◽  
Liquid Liquid Phase Separation
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