The role of liquid–liquid phase separation in regulating enzyme activity

O’Flynn, Brian G.; Mittag, Tanja

doi:10.1016/j.ceb.2020.12.012

Cited by 111 publications

(91 citation statements)

References 81 publications

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“…A wide range of biomolecules use low affinity, multivalent interactions to undergo liquid-liquid phase separation and generate membrane-less organelles, including the nucleolus, centrosomes, and processing bodies (reviewed in (Wheeler and Hyman, 2018)). The liquid-like properties of these bodies are thought to provide a local environment where specialized molecules are enriched and others are excluded, thus either enhancing or inhibiting the activity of specific biosynthetic pathways (reviewed in (Banani et al, 2017;O'Flynn and Mittag, 2021)). However, it remains generally difficult to demonstrate firmly whether the condensate nature of bodies is determinant for their function -the mere fact that a set of proteins undergoes phase separation in vitro is no proof that they also do so in vivo.…”

Section: Discussionmentioning

confidence: 99%

High interaction valency ensures cohesion and persistence of a microtubule +TIP body at the plus-end of a single specialized microtubule in yeast

Meier

Farcas

Kumar

et al. 2021

Preprint

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Microtubule plus-end tracking proteins (+TIPs) control microtubule specialization and are as such essential notably during eukaryotic cell division. Here, we investigated interactions and functions of the budding yeast Kar9 network consisting of the core +TIPs components Kar9 (functional homologue of APC, MACF, and SLAIN), Bim1 (orthologue of EB1), and Bik1 (orthologue of CLIP-170). Our data indicate that a redundant, multivalent web of interactions links the three +TIPs together to form a "Kar9 body" at the tip of a single cytoplasmic microtubule. They further suggest that this body is a liquid-like condensate, allowing it to persist on both growing and shrinking microtubule tips, and functions as a mechanical coupling device between microtubules and actin cables during mitosis. Our study underlines the power of dissecting the web of low-affinity interactions driving liquid-liquid phase separation of proteins in order to demonstrate the importance and establish the functional roles of condensation processes in vivo.

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Section: Discussionmentioning

confidence: 99%

High interaction valency ensures cohesion and persistence of a microtubule +TIP body at the plus-end of a single specialized microtubule in yeast

Meier

Farcas

Kumar

et al. 2021

Preprint

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“…Another way that cells achieve internal organization is via liquid-liquid phase separation (LLPS), in which the physical and chemical properties of certain molecules cause them to preferentially self-associate, separating from the cellular milieu [3][4][5][6][7][8][9][10][11][12]. These phase-separated condensates, termed membraneless organelles, are formed by proteins and nucleic acids and are linked to a variety of cellular activities, as well as many pathological states [3][4][5][6][7][8][9][10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Higher-order organization of biomolecular condensates

et al. 2021

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A guiding principle of biology is that biochemical reactions must be organized in space and time. One way this spatio-temporal organization is achieved is through liquid–liquid phase separation (LLPS), which generates biomolecular condensates. These condensates are dynamic and reactive, and often contain a complex mixture of proteins and nucleic acids. In this review, we discuss how underlying physical and chemical processes generate internal condensate architectures. We then outline the diverse condensate architectures that are observed in biological systems. Finally, we discuss how specific condensate organization is critical for specific biological functions.

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“…Various cellular processes occur in specialized compartments that can be membrane-surrounded organelles or biomolecular condensates formed by liquid–liquid phase separation (LLPS) (reviewed in ( 1 , 2 , 3 )). On the molecular level, phase separation can be induced by intermolecular interactions between modular binding domains and cognate peptide motifs ( 4 , 5 ).…”

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confidence: 99%

The N-terminal domain of the prion protein is required and sufficient for liquid–liquid phase separation: A crucial role of the Aβ-binding domain

Kamps

Lin

Oliva

et al. 2021

Journal of Biological Chemistry

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Formation of biomolecular condensates through liquid–liquid phase separation (LLPS) has been described for several pathogenic proteins linked to neurodegenerative diseases and is discussed as an early step in the formation of protein aggregates with neurotoxic properties. In prion diseases, neurodegeneration and formation of infectious prions is caused by aberrant folding of the cellular prion protein (PrP C ). PrP C is characterized by a large intrinsically disordered N-terminal domain and a structured C-terminal globular domain. A significant fraction of mature PrP C is proteolytically processed in vivo into an entirely unstructured fragment, designated N1, and the corresponding C-terminal fragment C1 harboring the globular domain. Notably, N1 contains a polybasic motif that serves as a binding site for neurotoxic Aβ oligomers. PrP can undergo LLPS; however, nothing is known how phase separation of PrP is triggered on a molecular scale. Here, we show that the intrinsically disordered N1 domain is necessary and sufficient for LLPS of PrP. Similar to full-length PrP, the N1 fragment formed highly dynamic liquid-like droplets. Remarkably, a slightly shorter unstructured fragment, designated N2, which lacks the Aβ-binding domain and is generated under stress conditions, failed to form liquid-like droplets and instead formed amorphous assemblies of irregular structures. Through a mutational analysis, we identified three positively charged lysines in the postoctarepeat region as essential drivers of condensate formation, presumably largely via cation–π interactions. These findings provide insights into the molecular basis of LLPS of the mammalian prion protein and reveal a crucial role of the Aβ-binding domain in this process.

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The role of liquid–liquid phase separation in regulating enzyme activity

Cited by 111 publications

References 81 publications

High interaction valency ensures cohesion and persistence of a microtubule +TIP body at the plus-end of a single specialized microtubule in yeast

High interaction valency ensures cohesion and persistence of a microtubule +TIP body at the plus-end of a single specialized microtubule in yeast

Higher-order organization of biomolecular condensates

The N-terminal domain of the prion protein is required and sufficient for liquid–liquid phase separation: A crucial role of the Aβ-binding domain

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