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 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.

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 The phase separation-dependent FUS interactome reveals nuclear and cytoplasmic function of liquid-liquid phase separation

2019 ◽  
Author(s):  
Stefan Reber ◽  
Helen Lindsay ◽  
Anny Devoy ◽  
Daniel Jutzi ◽  
Jonas Mechtersheimer ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Rna Binding ◽  
Mitochondrial Gene ◽  
Liquid Phase Separation ◽  
Fused In Sarcoma ◽  
Damage Repair ◽  
Interaction Partners ◽  
Lateral Sclerosis ◽  
Liquid Liquid Phase Separation

AbstractLiquid-liquid phase separation (LLPS) of proteins and RNAs has emerged as the driving force underlying the formation of membrane-less organelles. Such biomolecular condensates have various biological functions and have been linked to disease. One of the best studied proteins undergoing LLPS is Fused in Sarcoma (FUS), a predominantly nuclear RNA-binding protein. Mutations in FUS have been causally linked to Amyotrophic Lateral Sclerosis (ALS), an adult-onset motor neuron disease, and LLPS followed by aggregation of cytoplasmic FUS has been proposed to be a crucial disease mechanism. In spite of this, it is currently unclear how LLPS impacts the behaviour of FUS in cells, e.g. its interactome. In order to study the consequences of LLPS on FUS and its interaction partners, we developed a method that allows for the purification of phase separated FUS-containing droplets from cell lysates. We observe substantial alterations in the interactome of FUS, depending on its biophysical state. While non-phase separated FUS interacts mainly with its well-known interaction partners involved in pre-mRNA processing, phase-separated FUS predominantly binds to proteins involved in chromatin remodelling and DNA damage repair. Interestingly, factors with function in mitochondria are strongly enriched with phase-separated FUS, providing a potential explanation for early changes in mitochondrial gene expression observed in mouse models of ALS-FUS. In summary, we present a methodology that allows to investigate the interactome of phase-separating proteins and provide evidence that LLPS strongly shapes the FUS interactome with important implications for function and disease.

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

scholarly journals Amyloid Aggregation under the Lens of Liquid–Liquid Phase Separation

2020 ◽  
pp. 368-378
Author(s):  
Yanting Xing ◽  
Aparna Nandakumar ◽  
Aleksandr Kakinen ◽  
Yunxiang Sun ◽  
Thomas P. Davis ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Amyloid Aggregation ◽  
Liquid Liquid Phase Separation
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