Proteins with prion-like domains can form viscoelastic condensates that enable membrane remodeling and endocytosis

Bergeron-Sandoval, Louis-Philippe; Kumar, Sandeep; Heris, Hossein K.; Chang, Catherine; Cornell, Caitlin E.; Keller, Sarah L.; François, Paul; Hendricks, Adam G.; Ehrlicher, Allen J.; Pappu, Rohit V.; Michnick, Stephen W.

doi:10.1101/145664

Cited by 48 publications

(38 citation statements)

References 60 publications

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“…3C). The droplet's interfacial energy is favorable up to an invagination depth of~80 nm, close to the range that the CCP moves before scission (~100 nm) [110,140], totaling 1000 k B T [139]. However, the interfacial energy minimum is reached at an invagination depth of~40 nm, which falls short of the expected invagination depth [139].…”

Section: Liquid Phase Separationmentioning

confidence: 72%

“…The droplet's interfacial energy is favorable up to an invagination depth of ~ 80 nm, close to the range that the CCP moves before scission (~ 100 nm) , totaling ~ 1000 k B T . However, the interfacial energy minimum is reached at an invagination depth of ~ 40 nm, which falls short of the expected invagination depth . Furthermore, it remains unclear exactly what causes, disrupts, maintains, or contributes to phase‐separated droplet formation within endocytic structures and it is especially difficult to experimentally probe the dynamic stability of droplets in endocytosis, given that the process is out of equilibrium and completed within seconds.…”

Section: Other Putative Mechanismsmentioning

confidence: 96%

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Molecular mechanisms of force production in clathrin‐mediated endocytosis

et al. 2018

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During clathrin-mediated endocytosis (CME), a flat patch of membrane is invaginated and pinched off to release a vesicle into the cytoplasm. In yeast CME, over 60 proteins—including a dynamic actin meshwork—self-assemble to deform the plasma membrane. Several models have been proposed for how actin and other molecules produce the forces necessary to overcome the mechanical barriers of membrane tension and turgor pressure, but the precise mechanisms and a full picture of their interplay are still not clear. In this review, we discuss the evidence for these force production models from a quantitative perspective and propose future directions for experimental and theoretical work that could clarify their various contributions.

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Section: Liquid Phase Separationmentioning

confidence: 72%

Section: Other Putative Mechanismsmentioning

confidence: 96%

Molecular mechanisms of force production in clathrin‐mediated endocytosis

et al. 2018

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“…In the case of Ede1, the coiled-coil and disordered domains are important for its phase separation properties. Many other endocytic proteins have unstructured (Dafforn and Smith, 2004;Kalthoff et al, 2002) and prion-like (Alberti et al, 2009) regions that may have a tendency to phase separate, and recent studies suggested that the unstructured protein regions can generate force for membrane bending during vesicle budding (Bergeron-Sandoval et al, 2018;Busch et al, 2015;Snead et al, 2017).…”

Section: Other Roles For Phase Separation In Endocytosismentioning

confidence: 99%

Phase separation of Ede1 promotes the initiation of endocytic events

Kozak

Kaksonen

2019

Preprint

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Clathrin-mediated endocytosis is a major pathway that eukaryotic cells use to produce transport vesicles from the plasma membrane. The assembly of the endocytic coat is initiated by a dynamic network of weakly interacting proteins, but the exact mechanism of initiation is unknown. Ede1, the yeast homologue of mammalian Eps15, is one of the early-arriving endocytic proteins and a key initiation factor. In the absence of Ede1, most other early endocytic proteins lose their punctate localization and the frequency of endocytic initiation is decreased. We show here that in mutants with increased amounts of cytoplasmic Ede1, the excess protein forms large condensates which exhibit properties of phase separated liquid protein droplets. These Ede1 condensates recruit many other early-arriving endocytic proteins. Their formation depends on the core region of Ede1 that contains a coiled coil and a low-complexity domain. We demonstrate that Ede1 core region is essential for the endocytic function of Ede1. The core region can also promote clustering of a heterologous lipid-binding domain into discrete sites on the plasma membrane that initiate endocytic events. We propose that the clustering of the early endocytic proteins and cargo depend on phase separation mediated by Ede1.

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“…Whereas these long-known, floating droplet or-ganelles are large enough to be visible using simpler light microscopic techniques, in the past years liquid-liquid phase separation has been implicated in multifarious processes in which – often sub-micrometer-sized – condensates are formed at particular sites in the cell: at sites of DNA repair foci (Altmeyer et al, 2015), Polycomb-mediated chromatin silencing (Tatavosian et al, 2019), transmembrane signalling (Banjade and Rosen, 2014; Case et al, 2019), microtubule formation (So et al, 2019; Huang et al, 2018; Hernández-Vega et al, 2017; Jiang et al, 2015), actin polymerization (Weirich et al, 2017), endocytosis (Bergeron-Sandoval et al, 2017; Miao et al, 2018), transcription (Cho et al, 2018; Sabari et al, 2018; Chong et al, 2018; Boehning et al, 2018), at presynaptic active zones (Wu et al, 2019; Zeng et al, 2018), and for RNP transport (Formicola et al, 2019; Alami et al, 2014). Such localized condensates form upon a local stimulus to recruit the required set of proteins and are dissolved once the job is done.…”

mentioning

confidence: 99%

Mechanisms of active regulation of biomolecular condensates

Soeding

Zwicker

Sohrabi-Jahromi

et al. 2019

Preprint

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Liquid-liquid phase separation is a key organizational principle in eukaryotic cells, on par with intracellular membranes. It allows cells to concentrate specific proteins into condensates, increasing reaction rates and achieving switch-like regulation. However, it is unclear how cells trigger condensate formation or dissolution and regulate their sizes. We predict from first principles two mechanisms of active regulation by post-translational modifications such as phosphorylation: In enrichment-inhibition, the regulating modifying enzyme enriches in condensates and the modifications of proteins inhibit their interactions. Stress granules, Cajal bodies, P granules, splicing speckles, and synapsin condensates obey this model. In localization-induction, condensates form around an immobilized modifying enzyme, whose modifications strengthen protein interactions. Spatially targeted condensates formed during transmembrane signaling, microtubule assembly, and actin polymerization conform to this model. The two models make testable predictions that can guide studies into the many emerging roles of biomolecular condensates. Eukaryotic cells contain numerous types of mem-1 braneless organelles, which contain between a few 2 and thousands of protein and RNA species that are 3 highly enriched in comparison to the surrounding nu-4 cleoplasm or cytoplasm. These biomolecular conden-5 sates are held together by weak, multivalent and highly 6 collaborative interactions, often between intrinsically 7 54 active promoters. Here, we propose two active mecha-55 nisms used by cells for these purposes.56 Phase separation and condensate size behaviour 57 To keep the model simple, we consider only one type of 58 condensate protein. In the dilute regime below the sat-59 1 Cellular control of liquid droplet formation, size, and localization • July 5, 2019 Figure 1: Phase separation and condensate droplet size behaviour. A When protein-protein and solvent-solventinteractions are more favorable than protein-solvent interactions, demixing into two phases can occur, a dilute phase with low protein concentration c out and a dense phase with high concentration c in . This happens when the sum of free energies of the two phases is lower (tip of blue arrow) than the energy of the single phase (base of blue arrow) . B c out is the limiting concentration for infinite condensate droplet radius R. The concentration on the outside of a condensate of radius R is larger the smaller the condensate is (green double-headed arrows), as it cannot hold on to its proteins as well as large ones. This leads to a concentration gradient (∇concentration), which fuels a diffusive flux from small to large condensates (wiggly arrows). (l c is a measure of interaction strength between proteins in comparison to the solvent.) C As a result, condensates below a radius R crit will shrink and larger ones will grow. uration protein concentration c out , condensate droplets 60 cannot form ( Figure 1A). Above c out , in the phase sepa-61 ration regime, condensates can be stable...

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Proteins with prion-like domains can form viscoelastic condensates that enable membrane remodeling and endocytosis

Cited by 48 publications

References 60 publications

Molecular mechanisms of force production in clathrin‐mediated endocytosis

Molecular mechanisms of force production in clathrin‐mediated endocytosis

Phase separation of Ede1 promotes the initiation of endocytic events

Mechanisms of active regulation of biomolecular condensates

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