Physical Principles Underlying the Complex Biology of Intracellular Phase Transitions

Annual Review of Biophysics, Journal Year: 2020, Volume and Issue: 49(1), P. 107 - 133

Published: Jan. 31, 2020

Many biomolecular condensates appear to form via spontaneous or driven processes that have the hallmarks of intracellular phase transitions. This suggests a common underlying physical framework might govern formation functionally and compositionally unrelated condensates. In this review, we summarize recent work leverages stickers-and-spacers adapted from field associative polymers for understanding how multivalent protein RNA molecules drive transitions give rise We discuss valence stickers impacts driving forces condensate elaborate on can be distinguished spacers in different contexts. touch impact sticker- spacer-mediated interactions rheological properties show model mapped known drivers types

Language: Английский

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Modulation of cellular processes by histone and non-histone protein acetylation

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(5), P. 329 - 349

Published: Jan. 18, 2022

Language: Английский

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A current view on Tau protein phosphorylation in Alzheimer's disease

Current Opinion in Neurobiology, Journal Year: 2021, Volume and Issue: 69, P. 131 - 138

Published: April 21, 2021

The functions of the neuronal microtubule-associated protein Tau in central nervous system are regulated by manifold posttranslational modifications at more than 50 sites. healthy neurons carries multiple phosphate groups, mostly its microtubule assembly domain. Elevated phosphorylation and aggregation widely considered pathological hallmarks Alzheimer's disease (AD) other tauopathies, triggering quest for context. However, patterns physiological surprisingly similar heterogenous, making it difficult to identify specific as therapeutic targets biomarkers AD. We present a concise summary - view on important previous recent advances analysis context

Language: Английский

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Liquid-liquid phase separation induces pathogenic tau conformations in vitro

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: June 4, 2020

Formation of membrane-less organelles via liquid-liquid phase separation is one way cells meet the biological requirement for spatiotemporal regulation cellular components and reactions. Recently, tau, a protein known its involvement in Alzheimer's disease other tauopathies, was found to undergo making it several proteins associated with neurodegenerative diseases do so. Here, we demonstrate that tau forms dynamic liquid droplets vitro at physiological levels upon molecular crowding buffers resemble conditions. Tau droplet formation significantly enhanced by disease-associated modifications, including AT8 phospho-epitope P301L mutation linked an inherited tauopathy. Moreover, dynamics are reduced these modified tau. Extended promoted time-dependent adoption toxic conformations oligomerization, but not filamentous aggregation. showed greatest oligomer following extended separation. These findings suggest may facilitate non-filamentous pathogenic conformations.

Language: Английский

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Prebiotic Peptides: Molecular Hubs in the Origin of Life

Chemical Reviews, Journal Year: 2020, Volume and Issue: 120(11), P. 4707 - 4765

Published: Feb. 26, 2020

The fundamental roles that peptides and proteins play in today's biology makes it almost indisputable were key players the origin of life. Insofar as is appropriate to extrapolate back from extant prebiotic world, one must acknowledge critical importance interconnected molecular networks, likely with components, would have played life's origin. In this review, we summarize chemical processes involving could contributed early evolution, an emphasis on interactions between other classes organic molecules. We first mechanisms by which amino acids similar building blocks been produced elaborated into proto-peptides. Next, non-covalent well nucleic acids, lipids, carbohydrates, metal ions, aromatic molecules are discussed relation possible such evolution structure function. Finally, describe research structural alternatives covalent adducts acids/peptides propose ample future breakthroughs origin-of-life chemistry will stem investigations systems synergistic different emerge.

Language: Английский

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Tunable multiphase dynamics of arginine and lysine liquid condensates

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Sept. 15, 2020

Liquid phase separation into two or more coexisting phases has emerged as a new paradigm for understanding subcellular organization, prebiotic life, and the origins of disease. The design principles underlying biomolecular have potential to drive development novel liquid-based organelles therapeutics, however, an how individual molecules contribute emergent material properties, approaches directly manipulate dynamics are lacking. Here, using microrheology, we demonstrate that droplets poly-arginine coassembled with mono/polynucleotides approximately 100 fold greater viscosity than comparable lysine droplets, both which can be finer tuned by polymer length. We find these amino acid-level differences formation immiscible tunable kinetics further exploited trigger controlled release droplet components. Together, this work provides mechanism leveraging sequence-level components in order regulate multiphase coexistence.

Language: Английский

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Arginine-Enriched Mixed-Charge Domains Provide Cohesion for Nuclear Speckle Condensation

Molecular Cell, Journal Year: 2020, Volume and Issue: 77(6), P. 1237 - 1250.e4

Published: Feb. 11, 2020

Language: Английский

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The Role of Post-Translational Modifications in the Phase Transitions of Intrinsically Disordered Proteins

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(21), P. 5501 - 5501

Published: Nov. 5, 2019

Advances in genomics and proteomics have revealed eukaryotic proteomes to be highly abundant intrinsically disordered proteins that are susceptible diverse post-translational modifications. Intrinsically regions critical the liquid–liquid phase separation facilitates specialized cellular functions. Here, we discuss how modifications of protein segments can regulate molecular condensation macromolecules into functional phase-separated complexes.

Language: Английский

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Mechanisms for Active Regulation of Biomolecular Condensates

Trends in Cell Biology, Journal Year: 2019, Volume and Issue: 30(1), P. 4 - 14

Published: Nov. 18, 2019

Language: Английский

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Formation of Multiphase Complex Coacervates and Partitioning of Biomolecules within them

Biomacromolecules, Journal Year: 2019, Volume and Issue: 21(2), P. 630 - 640

Published: Nov. 19, 2019

Biological systems employ liquid–liquid phase separation to localize macromolecules and processes. The properties of intracellular condensates that allow for multiple, distinct liquid compartments the impact their coexistence on composition solute partitioning are not well understood. Here, we generate two three coexisting macromolecule-rich by complex coacervation based ion pairing in mixtures contain or polyanions together with one, two, polycations. While some polyelectrolyte order-of-addition was important achieve phases, others it not, suggesting observed multiphase droplet morphologies energetically favorable. Polyelectrolytes were distributed across all coacervate depending relative interactions between them, which turn impacted oligonucleotide oligopeptide solutes. These results show ease generating coacervates ability tune via sharing inherent systems.

Language: Английский

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