The material properties of a bacterial-derived biomolecular condensate tune biological function in natural and synthetic systems

Lasker, Keren; Boeynaems, Steven; Lam, Vinson; Scholl, Daniel; Stainton, Emma; Briner, Adam; Jacquemyn, Maarten; Daelemans, Dirk; Deniz, Ashok A.; Villa, Elizabeth; Holehouse, Alex S.; Gitler, Aaron D.; Shapiro, Lucy

doi:10.1038/s41467-022-33221-z

Cited by 61 publications

(73 citation statements)

References 97 publications

(112 reference statements)

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“…Yet experiments show that a crowded environment can influence the appearance of pathological fibrillar states within biomolecular condensates. [68][69][70][71] It has also been found that the material properties of BCs are important for their cellular functions, [34,37] and disordered protein domains can exert steric pressure on cellular membranes. [72] Predicting the response of condensed phases of IDPs to the crowdedness of their environment is an important step in understanding their functions in health and possible role in treating diseases.…”

Section: Discussionmentioning

confidence: 99%

“…[29][30][31] A better understanding of how BCs are coupled (or not) to their crowded environment would assist in deciphering their cellular roles and constructing synthetic BCs. [32][33][34][35][36][37][38] The complexity of living cells has driven research on model condensates, which typically use unphysiologically-high concentrations of one, or at most a few, species of IDP in buffer, although their relevance to living cells has been strongly questioned. [39,40] An example is provided by in vitro experiments on the protein Fused in Sarcoma (FUS), an RNA-binding protein that is implicated in the neurodegenerative disease ALS.…”

Section: Introductionmentioning

confidence: 99%

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Macromolecular crowding is surprisingly unable to deform the structure of a model biomolecular condensate

Shillcock

Thomas

Ipsen

et al. 2022

Preprint

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The crowded interior of a living cell makes experiments on simpler systems attractive. Although these reveal interesting phenomena, their biological relevance can be questionable. A topical example is the phase separation of intrinsically disordered proteins into biomolecular condensates, which is proposed to underlie the membraneless compartmentalisation of many cellular functions. How a cell reliably controls biochemical reactions in compartments open to the compositionally varying cytoplasm is an important question for understanding cellular homeostasis. Computer simulations are often used to study the phase behaviour of model biomolecular condensates, but the number of relevant parameters explodes as the number of protein components increases. It is unfeasible to exhaustively simulate such models for all parameter combinations, although interesting phenomena are almost certainly hidden in the jungle of their high dimensional parameter space. Here we have studied the phase behaviour of a model biomolecular condensate in the presence of a polymeric crowding agent. We used a novel compute framework to execute dozens of simultaneous simulations spanning the protein crowder concentration space. We then combined the results into a graphical representation for human interpretation, which provided an efficient way to search the high-dimensional parameter space. We found that steric repulsion from the crowder drives a near-critical system across the phase boundary, but the molecular arrangement within the resulting biomolecular condensate is rather insensitive to the crowder concentration and molecular weight. We propose that a cell may use the local cytoplasmic concentration to assist formation of biomolecular condensates, while relying on the dense phase reliably providing a stable, structured, fluid milieu for cellular biochemistry despite being open to its changing environment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Macromolecular crowding is surprisingly unable to deform the structure of a model biomolecular condensate

Shillcock

Thomas

Ipsen

et al. 2022

Preprint

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“…Its N‐terminal region binds clients through a short conserved helix (Holmes et al, 2016 ; Nordyke et al, 2020 ). The central region of PopZ is disordered with many prolines and negatively charged amino acids and likely acts as a tuner of PopZ material properties (Lasker et al, 2022 ). Self‐assembly is mediated by interactions between three helices at the C‐terminal helical region (Figure 2a,b ; Bowman et al, 2010 ; Bowman et al, 2013 ; Laloux & Jacobs‐Wagner, 2013 ; Lasker et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Integrative visualization of the molecular structure of a cellular microdomain

Goodsell

Lasker

2023

Protein Science

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An integrative approach to visualization is used to create a visual snapshot of the structural biology of the polar microdomain of Caulobacter crescentus . The visualization is based on the current state of molecular and cellular knowledge of the microdomain and its cellular context. The collaborative process of researching and executing the visualization has identified aspects that are well determined and areas that require further study. The visualization is useful for dissemination, education, and outreach, and the study lays the groundwork for future 3D modeling and simulation of this well‐studied example of a cellular condensate.

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“…Bio-polymer networks are ubiquitous in nature and play a vital role in (liquid-liquid phase separated) biomolecular condensates [1][2][3][4][5] and natural silk [6,7], as well as in artificial condensates [8] and novel soft materials such as hydrogels [9]. Reversible networks are typically constituted of intrinsically disordered protein (IDP) chains with 'sticker' patches that form intermolecular crosslinks, and 'spacer' sequences that covalently link the stickers within each protein chain.…”

Section: Introductionmentioning

confidence: 99%

“…Intriguingly, in different species of algae the binding components vary in amino acid sequence [17], which suggests pyrenoids may be optimised for different environmental conditions. Molecular design parameters are the sticker binding affinity, the flexibility of the spacers, and the sequence of the chains [8], and will affect the local structure around the rubisco holoenzyme, as depicted in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Competitive Binding of Force-Extensible Sticker-and-Spacer 'EPYC1' Polypeptides to a Patchy Colloidal 'Rubisco' Protein

Schaefer¹

2023

Preprint

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Bio-polymer networks are ubiquitous in nature and fulfil unique mechanical and biological functionalities that sensitively rely on the mesoscopic structure of the network. Understanding how these structures are encoded for by the bio-macromolecular building blocks would open up a powerful means to design novel soft materials, but remains hampered by the enormous complexity of the network down to the molecular level. We focus on the CO2-fixating 'pyrenoid' in eukaryotic algae as an exemplar bi-molecular network, which is composed of rigid 'Rubisco' holoenzymes with 8 binding sites to which any of the 5 'sticker strands' of the intrinsically disordered polypeptide (IDP) 'EPYC1' may bind. As a consequence, a Rubisco-IDP complex has 10 8 structurally different microstates whose expectation values depend on the concentration, sticker binding strength, and on the force-extensiblity of the IDPs. We present a statistical physics approach to tackle this challenge, and apply it to self-consistently model available (i) surface plasmon resonance data on the competitive binding of cleaved (single-sticker) EPYC1 and (ii) fluorescence correlation spectroscopy data on the binding of full (five-sticker) EPYC1 chains. Beyond the quantitative agreement between our model and the experiments, the model pins down the regime of binding affinities and provides quantitative predictions on the structure of the rubisco-EPYC1 complex. Thus, we present a predictive model that enables the parametrisation and screening of IDP sequences towards complex networks of associating (bio-)polymers.

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The material properties of a bacterial-derived biomolecular condensate tune biological function in natural and synthetic systems

Cited by 61 publications

References 97 publications

Macromolecular crowding is surprisingly unable to deform the structure of a model biomolecular condensate

Macromolecular crowding is surprisingly unable to deform the structure of a model biomolecular condensate

Integrative visualization of the molecular structure of a cellular microdomain

Competitive Binding of Force-Extensible Sticker-and-Spacer 'EPYC1' Polypeptides to a Patchy Colloidal 'Rubisco' Protein

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