Liquid–liquid phase separation in human health and diseases

Signal Transduction and Targeted Therapy, Год журнала: 2021, Номер 6(1)

Опубликована: Авг. 1, 2021

Abstract Emerging evidence suggests that liquid–liquid phase separation (LLPS) represents a vital and ubiquitous phenomenon underlying the formation of membraneless organelles in eukaryotic cells (also known as biomolecular condensates or droplets). Recent studies have revealed evidences indicate LLPS plays role human health diseases. In this review, we describe our current understanding summarize its physiological functions. We further development Additionally, review recently developed methods for studying LLPS. Although research is infancy—but fast-growing—it clear an essential pathophysiological conditions. This highlights need overview recent advances field to translate knowledge regarding into therapeutic discoveries.

Язык: Английский

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Phase separation of FSP1 promotes ferroptosis

Nature, Год журнала: 2023, Номер 619(7969), С. 371 - 377

Опубликована: Июнь 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.

Язык: Английский

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Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids

Chemical Reviews, Год журнала: 2021, Номер 121(13), С. 8285 - 8307

Опубликована: Июнь 17, 2021

This review will focus on the process of amyloid-type protein aggregation. Amyloid fibrils are an important hallmark misfolding diseases and therefore have been investigated for decades. Only recently, however, atomic or near-atomic resolution structures elucidated from various in vitro ex vivo obtained fibrils. In parallel, fibril formation has studied under highly artificial but comparatively reproducible conditions. The starts with a summary what is known speculated aggregation experiments. A partially hypothetic selection model be described that may suitable to explain why amyloid look way they do, particular, at least all so far reported high cryo-electron microscopy register, cross-β-sheet mostly consist two protofilaments twisted around each other. An intrinsic feature prion-like nature assemblies. Transferring point view situation not straightforward, hypothetic, leaves many open questions need addressed future.

Язык: Английский

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Phase separation in immune signalling

Nature reviews. Immunology, Год журнала: 2021, Номер 22(3), С. 188 - 199

Опубликована: Июль 6, 2021

Язык: Английский

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It’s not just a phase: function and characteristics of RNA-binding proteins in phase separation

Nature Structural & Molecular Biology, Год журнала: 2021, Номер 28(6), С. 465 - 473

Опубликована: Июнь 1, 2021

Язык: Английский

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Liquid–liquid phase separation in tumor biology

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Июль 8, 2022

Abstract Liquid–liquid phase separation (LLPS) is a novel principle for explaining the precise spatial and temporal regulation in living cells. LLPS compartmentalizes proteins nucleic acids into micron-scale, liquid-like, membraneless bodies with specific functions, which were recently termed biomolecular condensates. Biomolecular condensates are executors underlying intracellular spatiotemporal coordination of various biological activities, including chromatin organization, genomic stability, DNA damage response repair, transcription, signal transduction. Dysregulation these cellular processes key event initiation and/or evolution cancer, emerging evidence has linked formation to malignant transformations tumor biology. In this review, we comprehensively summarize detailed mechanisms condensate biophysical function review recent major advances toward elucidating multiple involved cancer cell pathology driven by aberrant LLPS. addition, discuss therapeutic perspectives research most developed drug candidates targeting modulation that can be used combat tumorigenesis.

Язык: Английский

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Stress granules, RNA-binding proteins and polyglutamine diseases: too much aggregation?

Cell Death and Disease, Год журнала: 2021, Номер 12(6)

Опубликована: Июнь 8, 2021

Abstract Stress granules (SGs) are membraneless cell compartments formed in response to different stress stimuli, wherein translation factors, mRNAs, RNA-binding proteins (RBPs) and other coalesce together. SGs assembly is crucial for survival, since implicated the regulation of translation, mRNA storage stabilization signalling, during stress. One defining feature their dynamism, as they quickly assembled upon then rapidly dispersed after source no longer present. Recently, dynamics, components functions have begun be studied context human diseases. Interestingly, regulated protein self-assembly that mediates SG formation contrasts with pathological aggregation a several neurodegenerative In particular, aberrant coalescence key polyglutamine (PolyQ) diseases, group nine disorders caused by an abnormal expansion PolyQ tract-bearing proteins, which increases propensity those aggregate. Available data concerning properties mutant disease-causing involvement dysregulation strongly suggests important role pathogenesis disorders. This review aims at discussing evidence supporting existence link between functionality disorders, focusing on biology way it can altered disease context.

Язык: Английский

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Conformational Dynamics of Intrinsically Disordered Proteins Regulate Biomolecular Condensate Chemistry

Chemical Reviews, Год журнала: 2022, Номер 122(6), С. 6719 - 6748

Опубликована: Фев. 18, 2022

Motions in biomolecules are critical for biochemical reactions. In cells, many reactions executed inside of biomolecular condensates formed by ultradynamic intrinsically disordered proteins. A deep understanding the conformational dynamics proteins is therefore utmost importance but complicated diverse obstacles. Here we review emerging data on motions liquidlike condensates. We discuss how liquid-liquid phase separation modulates internal across a wide range time and length scales. further highlight intermolecular interactions that not only drive appear as key determinants changes aging human diseases. The provides framework future studies to reveal regulation condensate chemistry.

Язык: Английский

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Conformational Expansion of Tau in Condensates Promotes Irreversible Aggregation

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(33), С. 13056 - 13064

Опубликована: Авг. 10, 2021

Liquid–liquid phase separation (LLPS) of proteins into biomolecular condensates has emerged as a fundamental principle underpinning cellular function and malfunction. Indeed, many human pathologies, including protein misfolding diseases, are linked to aberrant liquid-to-solid transitions, disease-associated aggregates often nucleate through separation. The molecular level determinants that promote pathological transitions remain, however, poorly understood. Here we study LLPS the microtubule-associated Tau, whose aggregation is associated with number neurodegenerative Alzheimer's disease. Using single molecule spectroscopy, probe directly conformational changes undergoes result LLPS. We perform single-molecule FRET fluorescence correlation spectroscopy experiments monitor intra- intermolecular demonstrate N- C-terminal regions Tau become extended, thus exposing microtubule-binding region. These facilitate interactions allow for formation nanoscale clusters Tau. Our results suggest these can fibrillization which be dramatically accelerated by disease-related mutations P301L P301S. findings provide important insights mechanism conversion from functional liquid assemblies aggregates.

Язык: Английский

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Modulating α-Synuclein Liquid–Liquid Phase Separation

Biochemistry, Год журнала: 2021, Номер 60(48), С. 3676 - 3696

Опубликована: Авг. 25, 2021

Liquid–liquid phase separation (LLPS) is a crucial phenomenon for the formation of functional membraneless organelles. However, LLPS also responsible protein aggregation in various neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease (PD). Recently, several reports, including ours, have shown that α-synuclein (α-Syn) undergoes subsequent liquid-to-solid transition, which leads to amyloid fibril formation. how environmental (and experimental) parameters modulate α-Syn remains elusive. Here, we show vitro strongly dependent on presence salts, allows charge neutralization at both terminal segments therefore promotes hydrophobic interactions supportive LLPS. Using purification methods experimental conditions, showed, depending upon either spontaneous (instantaneous) or delayed Furthermore, delineate kinetics liquid droplet (i.e., critical concentration time) relative can be modulated by salt/counterion concentration, pH, surface, PD-associated multivalent cations, N-terminal acetylation, are all known regulate vitro. Together, our observations suggest transition could pathological, triggered only under disease-associated conditions (high and/or promoting self-assembly). This study will significantly improve understanding molecular mechanisms transition.

Язык: Английский

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