scholarly journals Unraveling Molecular Interactions in Liquid–Liquid Phase Separation of Disordered Proteins by Atomistic Simulations

2020 ◽  
Vol 124 (41) ◽  
pp. 9009-9016 ◽  
Author(s):  
Matteo Paloni ◽  
Rémy Bailly ◽  
Luca Ciandrini ◽  
Alessandro Barducci
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Molecular Interactions ◽  
Liquid Phase Separation ◽  
Disordered Proteins ◽  
Atomistic Simulations ◽  
Liquid Liquid Phase Separation

Charge pattern affects the structure and dynamics of polyampholyte condensates

2020 ◽  
Vol 22 (34) ◽  
pp. 19368-19375 ◽  
Author(s):  
Milan Kumar Hazra ◽  
Yaakov Levy
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Intrinsically Disordered Proteins ◽  
Liquid Phase Separation ◽  
Disordered Proteins ◽  
Internal Diffusion ◽  
Intrinsically Disordered ◽  
Structure And Dynamics ◽  
Liquid Liquid Phase Separation

The charge pattern of intrinsically disordered proteins affects the dynamics and internal diffusion of their condensate formed via liquid–liquid phase separation.

scholarly journals The Dynamism of Intrinsically Disordered Proteins in Liquid-Liquid Phase Separation

2020 ◽  
Vol 118 (3) ◽  
pp. 60a
Author(s):  
Samrat Mukhopadhyay ◽  
Anupa Majumdar ◽  
Priyanka Dogra ◽  
Shiny Maity ◽  
Ashish Joshi
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Intrinsically Disordered Proteins ◽  
Liquid Phase Separation ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Liquid Liquid Phase Separation

scholarly journals Role and therapeutic potential of liquid‒liquid phase separation in amyotrophic lateral sclerosis

2020 ◽  
Author(s):  
Donya Pakravan ◽  
Gabriele Orlando ◽  
Valérie Bercier ◽  
Ludo Van Den Bosch
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Phase Separation ◽  
Liquid Phase ◽  
Therapeutic Potential ◽  
Liquid Phase Separation ◽  
Disordered Proteins ◽  
Familial Als ◽  
Als Patients ◽  
Lateral Sclerosis ◽  
Liquid Liquid Phase Separation

Abstract Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to progressive paralysis. Although most cases are sporadic, ∼10% are familial. Similar proteins are found in aggregates in sporadic and familial ALS, and over the last decade, research has been focused on the underlying nature of this common pathology. Notably, TDP-43 inclusions are found in almost all ALS patients, while FUS inclusions have been reported in some familial ALS patients. Both TDP-43 and FUS possess ‘low-complexity domains’ (LCDs) and are considered as ‘intrinsically disordered proteins’ (IDPs), which form liquid droplets in vitro due to the weak interactions caused by the LCDs. Dysfunctional ‘liquid‒liquid phase separation’ (LLPS) emerged as a new mechanism linking ALS-related proteins to pathogenesis. Here, we review the current state of knowledge on ALS-related gene products associated with a proteinopathy and discuss their status as LLPS proteins. In addition, we highlight the therapeutic potential of targeting LLPS for treating ALS.

An intrinsically disordered pathological prion variant Y145Stop converts into self-seeding amyloids via liquid–liquid phase separation

2021 ◽  
Vol 118 (45) ◽  
pp. e2100968118
Author(s):  
Aishwarya Agarwal ◽  
Sandeep K. Rai ◽  
Anamika Avni ◽  
Samrat Mukhopadhyay
Keyword(s):  
Phase Transitions ◽  
Phase Separation ◽  
Liquid Phase ◽  
Phase Behavior ◽  
Intrinsically Disordered Proteins ◽  
Liquid Phase Separation ◽  
Disordered Proteins ◽  
Cell Physiology ◽  
Intrinsically Disordered ◽  
Liquid Liquid Phase Separation

Biomolecular condensation via liquid–liquid phase separation of intrinsically disordered proteins/regions (IDPs/IDRs) along with other biomolecules is proposed to control critical cellular functions, whereas aberrant phase transitions are associated with a range of neurodegenerative diseases. Here, we show that a disease-associated stop codon mutation of the prion protein (PrP) at tyrosine 145 (Y145Stop), resulting in a truncated, highly disordered, N-terminal IDR, spontaneously phase-separates into dynamic liquid-like droplets. Phase separation of this highly positively charged N-terminal segment is promoted by the electrostatic screening and a multitude of weak, transient, multivalent, intermolecular interactions. Single-droplet Raman measurements, in conjunction with an array of bioinformatic, spectroscopic, microscopic, and mutagenesis studies, revealed a highly mobile internal organization within the liquid-like condensates. The phase behavior of Y145Stop is modulated by RNA. Lower RNA:protein ratios promote condensation at a low micromolar protein concentration under physiological conditions. At higher concentrations of RNA, phase separation is abolished. Upon aging, these highly dynamic liquid-like droplets gradually transform into ordered, β-rich, amyloid-like aggregates. These aggregates formed via phase transitions display an autocatalytic self-templating characteristic involving the recruitment and binding-induced conformational conversion of monomeric Y145Stop into amyloid fibrils. In contrast to this intrinsically disordered truncated variant, the wild-type full-length PrP exhibits a much lower propensity for both condensation and maturation into amyloids, hinting at a possible protective role of the C-terminal domain. Such an interplay of molecular factors in modulating the protein phase behavior might have much broader implications in cell physiology and disease.

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