Organization, dynamics and mechanoregulation of integrin-mediated cell–ECM adhesions

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 24(2), P. 142 - 161

Published: Sept. 27, 2022

Language: Английский

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The molecular basis for cellular function of intrinsically disordered protein regions

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 187 - 211

Published: Nov. 13, 2023

Language: Английский

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Phase Transitions of Associative Biomacromolecules

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(14), P. 8945 - 8987

Published: March 7, 2023

Multivalent proteins and nucleic acids, collectively referred to as multivalent associative biomacromolecules, provide the driving forces for formation compositional regulation of biomolecular condensates. Here, we review key concepts phase transitions aqueous solutions specifically that include folded domains intrinsically disordered regions. The these systems come under rubric coupled segregative transitions. underlying processes are presented, their relevance condensates is discussed.

Language: Английский

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Phase separation of FSP1 promotes ferroptosis

Nature, Journal Year: 2023, Volume and Issue: 619(7969), P. 371 - 377

Published: June 28, 2023

Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers1-3. Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K NAD(P)H/H+ an electron donor, has been identified the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of cyst(e)ine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis4-6. To develop FSP1 inhibitors next-generation therapeutic inducers, here we performed small molecule library screen compound class 3-phenylquinazolinones (represented by icFSP1) potent inhibitors. We show that icFSP1, unlike iFSP1, first described on-target inhibitor5, does not competitively inhibit enzyme activity, but instead triggers subcellular relocalization from membrane condensation before induction, in synergism GPX4 inhibition. icFSP1-induced condensates droplet-like properties consistent phase separation, emerging widespread mechanism modulate biological activity7. N-terminal myristoylation, distinct amino acid residues intrinsically disordered, low-complexity regions were be essential for FSP1-dependent separation cells vitro. further demonstrate icFSP1 impairs growth induces tumours vivo. Hence, our results suggest exhibits unique action synergizes ferroptosis-inducing agents potentiate ferroptotic cell death response, thus providing rationale targeting efficient anti-cancer therapy.

Language: Английский

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Condensates formed by prion-like low-complexity domains have small-world network structures and interfaces defined by expanded conformations

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Dec. 13, 2022

Abstract Biomolecular condensates form via coupled associative and segregative phase transitions of multivalent macromolecules. Phase separation to percolation is one example such transitions. Here, we characterize molecular mesoscale structural descriptions formed by intrinsically disordered prion-like low complexity domains (PLCDs). These systems conform sticker-and-spacers architectures. Stickers are cohesive motifs that drive interactions through reversible crosslinking spacers affect the cooperativity overall macromolecular solubility. Our computations reproduce experimentally measured sequence-specific behaviors PLCDs. Within simulated condensates, networks inter-sticker crosslinks organize PLCDs into small-world topologies. The dimensions vary with spatial location, being most expanded at preferring be oriented perpendicular interface. results demonstrate even simple type macromolecule feature inhomogeneous organizations molecules interfacial features likely prime them for biochemical activity.

Language: Английский

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Engineering synthetic biomolecular condensates

Nature Reviews Bioengineering, Journal Year: 2023, Volume and Issue: 1(7), P. 466 - 480

Published: April 17, 2023

Language: Английский

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Phase separation of protein mixtures is driven by the interplay of homotypic and heterotypic interactions

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 8, 2023

Prion-like low-complexity domains (PLCDs) are involved in the formation and regulation of distinct biomolecular condensates that form via phase separation coupled to percolation. Intracellular often encompass numerous proteins with PLCDs. Here, we combine simulations experiments study mixtures PLCDs from two RNA-binding proteins, hnRNPA1 FUS. Using experiments, find 1:1 A1-LCD FUS-LCD undergo more readily than either on their own due complementary electrostatic interactions. Tie line analysis reveals stoichiometric ratios different components sequence-encoded interactions contribute jointly driving forces for condensate formation. Simulations also show spatial organization within is governed by relative strengths homotypic versus heterotypic We uncover rules how interaction sequence lengths modulate conformational preferences molecules at interfaces formed proteins.

Language: Английский

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Improved predictions of phase behaviour of intrinsically disordered proteins by tuning the interaction range

Open Research Europe, Journal Year: 2023, Volume and Issue: 2, P. 94 - 94

Published: Jan. 17, 2023

The formation and viscoelastic properties of condensates intrinsically disordered proteins (IDPs) is dictated by amino acid sequence solution conditions. Because the involvement biomolecular in cell physiology disease, advancing our understanding relationship between protein phase separation (PS) may have important implications formulation new therapeutic hypotheses. Here, we present CALVADOS 2, a coarse-grained model IDPs that accurately predicts conformational propensities to undergo PS for diverse sequences In particular, systematically study effect varying range nonionic interactions use findings improve temperature scale model. We further optimize residue-specific parameters against experimental data on 55 proteins, while also leveraging 70 hydrophobicity scales from literature avoid overfitting training data. Extensive testing shows chain compaction propensity length charge patterning, as well at different temperatures salt concentrations.

Language: Английский

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“Structure”-function relationships in eukaryotic transcription factors: The role of intrinsically disordered regions in gene regulation

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(21), P. 3970 - 3984

Published: Oct. 19, 2022

Language: Английский

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Interface of biomolecular condensates modulates redox reactions

Chem, Journal Year: 2023, Volume and Issue: 9(6), P. 1594 - 1609

Published: April 28, 2023

Language: Английский

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