The perinuclear region concentrates disordered proteins with predicted phase separation distributed in a 3D network of cytoskeletal filaments and organelles

2021 ◽  
pp. 119161
Author(s):  
Mariana Juliani do Amaral ◽  
Ivone de Andrade Rosa ◽  
Sarah Azevedo Andrade ◽  
Xi Fang ◽  
Leonardo Rodrigues Andrade ◽  
...  
Keyword(s):  
Phase Separation ◽  
Disordered Proteins ◽  
Perinuclear Region ◽  
3D Network

scholarly journals Solvent Exposure and Ionic Condensation Drive Fuzzy Dimerization of Disordered Heterochromatin Protein Sequence

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 915
Author(s):  
Jazelli Mueterthies ◽  
Davit A. Potoyan
Keyword(s):  
Phase Separation ◽  
Low Complexity ◽  
Nuclear Bodies ◽  
Disordered Proteins ◽  
Solvent Exposure ◽  
Ion Release ◽  
Dimer Formation ◽  
Eukaryotic Organisms

Proteins with low complexity, disordered sequences are receiving increasing attention due to their central roles in the biogenesis and regulation of membraneless organelles. In eukaryotic organisms, a substantial fraction of disordered proteins reside in the nucleus, thereby facilitating the formation of nuclear bodies, nucleolus, and chromatin compartmentalization. The heterochromatin family of proteins (HP1) is an important player in driving the formation of gene silenced mesoscopic heterochromatin B compartments and pericentric regions. Recent experiments have shown that the HP1a sequence of Drosophila melanogaster can undergo liquid-liquid phase separation under both in vitro and in vivo conditions, induced by changes of the monovalent salt concentration. While the phase separation of HP1a is thought to be the mechanism underlying chromatin compartmentalization, the molecular level mechanistic picture of salt-driven phase separation of HP1a has remained poorly understood. The disordered hinge region of HP1a is seen as the driver of salt-induced condensation because of its charge enriched sequence and post-translational modifications. Here, we set out to decipher the mechanisms of salt-induced condensation of HP1a through a systematic study of salt-dependent conformations of single chains and fuzzy dimers of disordered HP1a hinge sequences. Using multiple independent all-atom simulations with and without enhanced sampling, we carry out detailed characterization of conformational ensembles of disordered HP1a chains under different ionic conditions using various polymeric and structural measures. We show that the mobile ion release, enhancement of local transient secondary structural elements, and side-chain exposure to solvent are robust trends that accompany fuzzy dimer formation. Furthermore, we find that salt-induced changes in the ensemble of conformations of HP1a disordered hinge sequence fine-tune the inter-chain vs. self-chain interactions in ways that favor fuzzy dimer formation under low salt conditions in the agreement with condensation trends seen in experiments.

scholarly journals Simulation of FUS protein condensates with an adapted coarse-grained model

2020 ◽  
Author(s):  
Zakarya Benayad ◽  
Sören von Bülow ◽  
Lukas S. Stelzl ◽  
Gerhard Hummer
Keyword(s):  
Free Energy ◽  
Phase Separation ◽  
Potential Energy ◽  
Energy Function ◽  
Potential Energy Function ◽  
Scaling Factor ◽  
Coarse Grained ◽  
Disordered Proteins ◽  
General Strategy ◽  
Droplet Shape

AbstractDisordered proteins and nucleic acids can condense into droplets that resemble the membraneless organelles observed in living cells. MD simulations offer a unique tool to characterize the molecular interactions governing the formation of these biomolecular condensates, their physico-chemical properties, and the factors controlling their composition and size. However, biopolymer condensation depends sensitively on the balance between different energetic and entropic contributions. Here, we develop a general strategy to fine-tune the potential energy function for molecular dynamics simulations of biopolymer phase separation. We rebalance protein-protein interactions against solvation and entropic contributions to match the excess free energy of transferring proteins between dilute solution and condensate. We illustrate this formalism by simulating liquid droplet formation of the FUS low complexity domain (LCD) with a rebalanced MARTINI model. By scaling the strength of the nonbonded interactions in the coarse-grained MARTINI potential energy function, we map out a phase diagram in the plane of protein concentration and interaction strength. Above a critical scaling factor of αc ≈ 0.6, FUS LCD condensation is observed, where α = 1 and 0 correspond to full and repulsive interactions in the MARTINI model, respectively. For a scaling factor α = 0.65, we recover the experimental densities of the dilute and dense phases, and thus the excess protein transfer free energy into the droplet and the saturation concentration where FUS LCD condenses. In the region of phase separation, we simulate FUS LCD droplets of four different sizes in stable equilibrium with the dilute phase and slabs of condensed FUS LCD for tens of microseconds, and over one millisecond in aggregate. We determine surface tensions in the range of 0.01 to 0.4mN/m from the fluctuations of the droplet shape and from the capillary-wave-like broadening of the interface between the two phases. From the dynamics of the protein end-to-end distance, we estimate shear viscosities from 0.001 to 0.02Pas for the FUS LCD droplets with scaling factors α in the range of 0.625 to 0.75, where we observe liquid droplets. Significant hydration of the interior of the droplets keeps the proteins mobile and the droplets fluid.

scholarly journals Natural and designed proteins inspired by extremotolerant organisms can form condensates and attenuate apoptosis in human cells

2021 ◽  
Author(s):  
Mike T. Veling ◽  
Dan T. Nguyen ◽  
Nicole N. Thadani ◽  
Michela E. Oster ◽  
Nathan J. Rollins ◽  
...  
Keyword(s):  
Phase Separation ◽  
Intrinsically Disordered Proteins ◽  
Human Cells ◽  
Disordered Proteins ◽  
Cellular Protection ◽  
Intrinsically Disordered ◽  
Apoe Protein ◽  
Condensate Formation ◽  
Associated Proteins ◽  
Induced Apoptosis

ABSTRACTMany organisms can survive extreme conditions and successfully recover to normal life. This extremotolerant behavior has been attributed in part to repetitive, amphipathic, and intrinsically disordered proteins that are upregulated in the protected state. Here, we assemble a library of approximately 300 naturally-occurring and designed extremotolerance-associated proteins to assess their ability to protect human cells from chemically-induced apoptosis. We show that proteins from tardigrades, nematodes, and the Chinese giant salamander are apoptosis protective. Notably, we identify a region of the human ApoE protein with similarity to extremotolerance-associated proteins that also protects against apoptosis. This region mirrors the phase separation behavior seen with such proteins, like the tardigrade protein CAHS2. Moreover, we identify a synthetic protein, DHR81, that shares this combination of elevated phase separation propensity and apoptosis protection. Finally, we demonstrate that driving protective proteins into the condensate state increases apoptosis protection, and highlight the ability for DHR81 condensates to sequester caspase-7. Taken together, this work draws a link between extremotolerance-associated proteins, condensate formation, and human cellular protection.

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
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