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

---

Denaturing purifications demonstrate that PRC2 and other widely reported chromatin proteins do not appear to bind directly to RNA in vivo

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(7), P. 1271 - 1289.e12

Published: Feb. 21, 2024

Polycomb repressive complex 2 (PRC2) is reported to bind many RNAs and has become a central player in reports of how long non-coding (lncRNAs) regulate gene expression. Yet, there growing discrepancy between the biochemical evidence supporting specific lncRNA-PRC2 interactions functional demonstrating that PRC2 often dispensable for lncRNA function. Here, we revisit RNA binding by show may not occur vivo. Using denaturing purification vivo crosslinked RNA-protein complexes human mouse cell lines, observe loss detectable chromatin-associated proteins previously (CTCF, YY1, others), despite accurately mapping bona fide RNA-binding sites across others (SPEN, TET2, others). Taken together, these results argue critical re-evaluation broad role orchestrate various chromatin regulatory mechanisms.

Language: Английский

---

Fundamental Aspects of Phase-Separated Biomolecular Condensates

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(13), P. 8550 - 8595

Published: June 17, 2024

Biomolecular condensates, formed through phase separation, are upending our understanding in much of molecular, cell, and developmental biology. There is an urgent need to elucidate the physicochemical foundations behaviors properties biomolecular condensates. Here we aim fill this by writing a comprehensive, critical, accessible review on fundamental aspects phase-separated We introduce relevant theoretical background, present basis for computation experimental measurement condensate properties, give mechanistic interpretations terms interactions at molecular residue levels.

Language: Английский

---

PSPC1 exerts an oncogenic role in AML by regulating a leukemic transcription program in cooperation with PU.1

Cell stem cell, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

---

RNA polymerase II clusters form in line with surface condensation on regulatory chromatin

Molecular Systems Biology, Journal Year: 2021, Volume and Issue: 17(9)

Published: Sept. 1, 2021

Language: Английский

---

Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(19), P. 3438 - 3456.e12

Published: Sept. 21, 2023

Language: Английский

---

Hypoxia-induced circ-CDYL-EEF1A2 transcriptional complex drives lung metastasis of cancer stem cells from hepatocellular carcinoma

Cancer Letters, Journal Year: 2023, Volume and Issue: 578, P. 216442 - 216442

Published: Oct. 16, 2023

Language: Английский

---

Transcription regulation by biomolecular condensates

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 8, 2024

Language: Английский

---

Nuclear RNA homeostasis promotes systems-level coordination of cell fate and senescence

Cell stem cell, Journal Year: 2024, Volume and Issue: 31(5), P. 694 - 716.e11

Published: April 16, 2024

Language: Английский

---

Molecular Drivers of RNA Phase Separation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

RNA molecules are essential in orchestrating the assembly of biomolecular condensates and membraneless compartments cells. Many form via association with proteins containing specific binding motifs. However, recent reports indicate that low-complexity sequences can self-assemble into condensate phases without protein assistance. Divalent cations significantly influence thermodynamics dynamics condensates, which exhibit base-specific lower-critical solution temperatures (LCST). The precise molecular origins these remain elusive. In this study, we employ atomistic simulations to elucidate driving forces governing temperature-dependent phase behavior RNA, providing new insights LCST. Using tetranucleotides their chemically modified analogs, map condensates' equilibrium thermodynamic profiles structural ensembles across various ionic conditions. Our findings reveal magnesium ions promote LCST by inducing local order-disorder transitions within structures. Consistent experimental observations, demonstrate thermal stability follows Poly(G) > Poly(A) Poly(C) Poly(U) order shaped interplay base-stacking hydrogen bonding interactions. Furthermore, our show conditions post-translational modifications fine-tune self-assembly modulate physical properties. for organizing play critical roles cellular processes. While many through interactions between proteins, studies have shown certain This ability is influenced sequence composition presence like magnesium. detailed carried out systematic study how temperature affect condensation. We discovered a key role condense at lower promoting changes RNA. also revealed varies depending on sequence, guanine-rich being most stable. Additionally, demonstrated chemical properties condensates. provides forms highlights potential strategies control behavior, could implications understanding organization developing therapies.

Language: Английский

---