Developmental Cell, Год журнала: 2020, Номер 55(1), С. 69 - 83
Опубликована: Окт. 1, 2020
Язык: Английский
Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(10)
Опубликована: Март 2, 2021
Significance Phase transitions of multivalent macromolecules known as scaffolds help drive the formation functional biomolecular condensates in cells. The and dissolution is tightly regulated, aberrant phase behavior associated with disease. Here, we show that distinct types ligands can exert control over by binding to sites on scaffold molecules. We further extent direction regulation be inferred through direct measurements how impact boundaries. Our findings have broad implications for understanding modeling ligand-mediated cells designing novel molecules regulatory condensates.
Язык: Английский
Процитировано
150
Nature, Год журнала: 2024, Номер 626(8000), С. 897 - 904
Опубликована: Янв. 31, 2024
Язык: Английский
Процитировано
137
Nature Chemical Biology, Год журнала: 2022, Номер 18(12), С. 1298 - 1306
Опубликована: Июнь 27, 2022
Язык: Английский
Процитировано
116
Molecular Biomedicine, Год журнала: 2022, Номер 3(1)
Опубликована: Май 11, 2022
Abstract Liquid-liquid phase separation (LLPS) has received significant attention in recent biological studies. It refers to a phenomenon that biomolecule exceeds the solubility, condensates and separates itself from solution liquid like droplets formation. Our understanding of it also changed memebraneless organelles compartmentalization, muti-functional crucibles, reaction regulators. Although this been employed for variety processes, studies mainly focus on its physiological significance, comprehensive research underlying physical mechanism is limited. The characteristics side chains amino acids interaction tendency proteins function importantly regulating LLPS thus should be pay more on. In addition, importance post-translational modifications (PTMs) underestimated, despite their abundance crucial functions maintaining electrostatic balance. review, we first introduce driving forces protein secondary structures involved different cell life processes. Subsequently, summarize existing reports PTM regulation related analyze basic principles, hoping find some common relations between PTM. Finally, speculate several unreported PTMs may have impact basing findings.
Язык: Английский
Процитировано
105
Nature Communications, Год журнала: 2022, Номер 13(1)
Опубликована: Ноя. 28, 2022
Intrinsically disordered proteins rich in cationic amino acid groups can undergo Liquid-Liquid Phase Separation (LLPS) the presence of charge-balancing anionic counterparts. Arginine and Lysine are two most prevalent acids that LLPS, with arginine-rich observed to LLPS more readily than lysine-rich proteins, a feature commonly attributed arginine's ability form stronger cation-π interactions aromatic groups. Here, we show promote is independent partners, peptides, but not display re-entrant phase behavior at high salt concentrations. We further demonstrate hydrophobicity arginine determining factor giving rise reentrant tunable viscoelastic properties dense phase. Controlling arginine-induced using temperature concentration opens avenues for bioengineering stress-triggered biological phenomena drug delivery systems.
Язык: Английский
Процитировано
98
Nature Cell Biology, Год журнала: 2022, Номер 24(5), С. 625 - 632
Опубликована: Май 1, 2022
Dynamic morphological changes of intracellular organelles are often regulated by protein phosphorylation or dephosphorylation1-6. Phosphorylation modulates stereospecific interactions among structured proteins, but how it controls molecular unstructured proteins and regulates their macroscopic behaviours remains unknown. Here we determined the cell cycle-specific behaviour Ki-67, which localizes to nucleoli during interphase relocates chromosome periphery mitosis. Mitotic hyperphosphorylation disordered repeat domains Ki-67 generates alternating charge blocks in these increases propensity for liquid-liquid phase separation (LLPS). A phosphomimetic sequence sequences with enhanced blockiness underwent strong LLPS vitro induced formation vivo. Conversely, mitotic NPM1 diminished a block suppressed LLPS, resulting nucleolar dissolution. Cell can be modulated via enhancing reducing regions, rather than attaching phosphate groups specific sites.
Язык: Английский
Процитировано
90
Cell, Год журнала: 2023, Номер 186(22), С. 4936 - 4955.e26
Опубликована: Окт. 1, 2023
Intrinsically disordered regions (IDRs) represent a large percentage of overall nuclear protein content. The prevailing dogma is that IDRs engage in non-specific interactions because they are poorly constrained by evolutionary selection. Here, we demonstrate condensate formation and heterotypic distinct separable features an IDR within the ARID1A/B subunits mSWI/SNF chromatin remodeler, cBAF, establish "sequence grammars" underlying each contribution. Condensation driven uniformly distributed tyrosine residues, partner mediated non-random blocks rich alanine, glycine, glutamine residues. These concentrate specific cBAF protein-protein interaction network essential for localization activity. Importantly, human disease-associated perturbations ARID1B sequence grammars disrupt function cells. Together, these data identify contributions to remodeling explain how phase separation provides mechanism through which both genomic functional recruitment achieved.
Язык: Английский
Процитировано
90
Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(13)
Опубликована: Март 25, 2022
SignificanceA large subclass of biomolecular condensates are linked to RNA regulation and known as ribonucleoprotein (RNP) bodies. While extensive work has identified driving forces for condensate formation, relatively little is about that oppose assembly. Here, using a fungal RNP protein, Whi3, we show portion its intrinsically disordered, glutamine-rich region modulates phase separation by forming transient alpha helical structures promote the assembly dilute oligomers. These oligomers detour Whi3 proteins from condensates, thereby impacting separation, protein-to-RNA ratio in material properties condensates. Our findings how nanoscale conformational oligomerization equilibria can influence mesoscale equilibria.
Язык: Английский
Процитировано
80
Cell, Год журнала: 2024, Номер 187(8), С. 1889 - 1906.e24
Опубликована: Март 18, 2024
Nucleoli are multicomponent condensates defined by coexisting sub-phases. We identified distinct intrinsically disordered regions (IDRs), including acidic (D/E) tracts and K-blocks interspersed E-rich regions, as defining features of nucleolar proteins. show that the localization preferences proteins determined their IDRs types RNA or DNA binding domains they encompass. In vitro reconstitutions studies in cells showed how condensation, which combines complex coacervation components, contributes to organization. D/E contribute lowering pH co-condensates formed with RNAs vitro. cells, this sets up a gradient between nucleoli nucleoplasm. By contrast, juxta-nucleolar bodies, have different macromolecular compositions, featuring protein very charge profiles, values equivalent higher than Our findings compositional specificities generate physicochemical properties for condensates.
Язык: Английский
Процитировано
72
Journal of the American Chemical Society, Год журнала: 2023, Номер 145(19), С. 10548 - 10563
Опубликована: Май 5, 2023
Liquid–liquid phase separation of flexible biomolecules has been identified as a ubiquitous phenomenon underlying the formation membraneless organelles that harbor multitude essential cellular processes. We use nuclear magnetic resonance (NMR) spectroscopy to compare dynamic properties an intrinsically disordered protein (measles virus NTAIL) in dilute and dense phases at atomic resolution. By measuring 15N NMR relaxation different field strengths, we are able characterize dynamics crowded conditions amplitude timescale motional modes those present organelle. Although local backbone conformational sampling appears be largely retained, occurring on all detectable timescales, including librational, dihedral angle segmental, chainlike motions, considerably slowed down. Their relative amplitudes also drastically modified, with slower, chain-like motions dominating profile. In order provide additional mechanistic insight, performed extensive molecular simulations under self-crowding concentrations comparable found liquid phase. Simulation broadly reproduces impact condensed both free energy landscape kinetic interconversion between states. particular, experimentally observed reduction fastest component correlates higher levels intermolecular contacts or entanglement simulations, reducing space available this mode strongly conditions.
Язык: Английский
Процитировано
59