Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure DOI Creative Commons

K. Faysal,

James Walsh,

Nadine Renner

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Feb. 13, 2024

The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved medical use. Here, we investigate effect of lenacapavir on HIV stability and uncoating. We employ single particle approach that simultaneously measures content release lattice persistence. demonstrate lenacapavir's potent antiviral activity predominantly due to lethal hyperstabilisation resultant loss compartmentalisation. This study highlights disrupting metastability powerful strategy development novel antivirals.

Language: Английский

Ligand effects on phase separation of multivalent macromolecules DOI Creative Commons
Kiersten M. Ruff, Furqan Dar, Rohit V. Pappu

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(10)

Published: March 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.

Language: Английский

Citations

147
Conformational ensembles of the human intrinsically disordered proteome DOI
Giulio Tesei, Anna Ida Trolle, Nicolas Jonsson

et al.

Nature, Journal Year: 2024, Volume and Issue: 626(8000), P. 897 - 904

Published: Jan. 31, 2024

Language: Английский

Citations

133
Learning the chemical grammar of biomolecular condensates DOI
Henry R. Kilgore,

Richard A. Young

Nature Chemical Biology, Journal Year: 2022, Volume and Issue: 18(12), P. 1298 - 1306

Published: June 27, 2022

Language: Английский

Citations

116
Post-translational modifications in liquid-liquid phase separation: a comprehensive review DOI Creative Commons
Jingxian Li, Mengdi Zhang, Weirui Ma

et al.

Molecular Biomedicine, Journal Year: 2022, Volume and Issue: 3(1)

Published: May 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.

Language: Английский

Citations

99
Hydrophobicity of arginine leads to reentrant liquid-liquid phase separation behaviors of arginine-rich proteins DOI Creative Commons
Yuri Hong, Saeed Najafi,

Thomas M. Casey

et al.

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

Published: Nov. 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.

Language: Английский

Citations

94
Cell cycle-specific phase separation regulated by protein charge blockiness DOI Creative Commons

Hiroya Yamazaki,

Masatoshi Takagi, Hidetaka Kosako

et al.

Nature Cell Biology, Journal Year: 2022, Volume and Issue: 24(5), P. 625 - 632

Published: May 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.

Language: Английский

Citations

90
A disordered region controls cBAF activity via condensation and partner recruitment DOI Creative Commons
Ajinkya Patil, Amy R. Strom, João A. Paulo

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(22), P. 4936 - 4955.e26

Published: Oct. 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.

Language: Английский

Citations

84
Dilute phase oligomerization can oppose phase separation and modulate material properties of a ribonucleoprotein condensate DOI Creative Commons
Ian Seim, Ammon E. Posey, Wilton T. Snead

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(13)

Published: March 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.

Language: Английский

Citations

80
Competing interactions give rise to two-state behavior and switch-like transitions in charge-rich intrinsically disordered proteins DOI Creative Commons
Xiangze Zeng, Kiersten M. Ruff, Rohit V. Pappu

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(19)

Published: May 5, 2022

Significance Intrinsically disordered regions (IDRs) of proteins, when tethered to folded domains, function either as flexible tails or linkers between domains. Most IDRs are polyampholytes that comprise a mixture oppositely charged residues. Recent measurements showed the tendency arginine- and lysine-rich sequences behave very differently from one another. Using computer simulations, we show these differences determined by in free energies hydration, steric volumes, other considerations. Further, interplay electrostatic attractions favorable hydration creates distinct stable states for polyampholytic IDRs. These findings have implications switch-like transitions regulation effective concentrations interaction motifs

Language: Английский

Citations

71
SRRM2 organizes splicing condensates to regulate alternative splicing DOI
Shaohai Xu,

Soak-Kuan Lai,

Donald Yuhui Sim

et al.

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 50(15), P. 8599 - 8614

Published: Aug. 5, 2022

Abstract SRRM2 is a nuclear-speckle marker containing multiple disordered domains, whose dysfunction associated with several human diseases. Using mainly EGFP-SRRM2 knock-in HEK293T cells, we show that forms biomolecular condensates satisfying most hallmarks of liquid-liquid phase separation, including spherical shape, dynamic rearrangement, coalescence and concentration dependence supported by in vitro experiments. Live-cell imaging shows organizes nuclear speckles along the cell cycle. As bona-fide splicing factor present spliceosome structures, deficiency induces skipping cassette exons short introns weak splice sites, tending to change large protein domains. In THP-1 myeloid-like depletion compromises viability, upregulates differentiation markers, sensitizes cells anti-leukemia drugs. FES isoform attenuates innate inflammatory responses, MUC1 isoforms undergo shedding oncogenic properties. We conclude acts as scaffold organize speckles, regulating alternative immunity homeostasis.

Language: Английский

Citations

70