Head-to-Tail Polymerization in the Assembly of Biomolecular Condensates

Bienz, Mariann

doi:10.1016/j.cell.2020.07.037

Cited by 74 publications

(62 citation statements)

References 111 publications

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“…Our model incorporates dynamical clustering of signalling proteins to generate biomolecular foci with a high local protein concentration and, hence, high signalling activity. Similar dynamics have been described in a variety of different cellular processes 22 , such as the well-characterised Wnt signal transduction pathway 23 . Furthermore, related models, in which proteins diffuse in one dimension along DNA, and which contain specific regions where the protein has distinct binding/ unbinding behaviour, have been successfully used to model other biological phenomena (e.g.…”

Section: Discussionsupporting

confidence: 57%

Diffusion-mediated HEI10 coarsening can explain meiotic crossover positioning in Arabidopsis

et al. 2021

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In most organisms, the number and distribution of crossovers that occur during meiosis are tightly controlled. All chromosomes must receive at least one ‘obligatory crossover’ and crossovers are prevented from occurring near one another by ‘crossover interference’. However, the mechanistic basis of this phenomenon of crossover interference has remained mostly mysterious. Using quantitative super-resolution cytogenetics and mathematical modelling, we investigate crossover positioning in the Arabidopsis thaliana wild-type, an over-expressor of the conserved E3 ligase HEI10, and a hei10 heterozygous line. We show that crossover positions can be explained by a predictive, diffusion-mediated coarsening model, in which large, approximately evenly-spaced HEI10 foci grow at the expense of smaller, closely-spaced clusters. We propose this coarsening process explains many aspects of Arabidopsis crossover positioning, including crossover interference. Consistent with this model, we also demonstrate that crossover positioning can be predictably modified in vivo simply by altering HEI10 dosage, with higher and lower dosage leading to weaker and stronger crossover interference, respectively. As HEI10 is a conserved member of the RING finger protein family that functions in the interference-sensitive pathway for crossover formation, we anticipate that similar mechanisms may regulate crossover positioning in diverse eukaryotes.

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Section: Discussionsupporting

confidence: 57%

Diffusion-mediated HEI10 coarsening can explain meiotic crossover positioning in Arabidopsis

et al. 2021

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“…Proteins with intrinsically disordered protein regions (IDRs), repeats of short oligomerizing motifs, and nucleic acid chains are biopolymers that have been observed to promote condensate formation (Banani et al, 2016;Bienz, 2020;Gomes and Shorter, 2019;Harmon et al, 2017;Jain and Vale, 2017;Pak et al, 2016;Shrinivas et al, 2019) (Figure 2A). The formation of condensates, and selective partitioning of biomolecules into condensates, has been attributed to specific weak and dynamic interactions among the molecules, including salt bridges, pi-pi, pi-cation, and hydrophobic interactions (Brangwynne et al, 2015;Lin et al, 2017;Vernon et al, 2018; Wang et al, 2018) ( Figure 2B).…”

Section: Biomolecular Condensatesmentioning

confidence: 99%

Biomolecular Condensates and Cancer

2021

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“…Along these lines, our study suggests that the condensation pathway is driven by residues that are capable of multiple binding modes, which are often associated with conformationallyheterogeneous structural elements [26,47,58].…”

Section: Discussionmentioning

confidence: 72%

“…We compare the nature of the interactions along the condensation pathway between dropletpromoting regions and amyloid-promoting regions. We propose a model in which the condensation pathway is driven by conformationally heterogeneous elements, which have been referred to as labile structures [25,26]. Our analysis indicates the possibility of predicting aggregation-promoting mutations in droplet-forming proteins based on generic interactions and the ability of sequence elements to switch between different interactions modes.…”

Section: Introductionmentioning

confidence: 95%

Sequence determinants of the aggregation of proteins within condensates generated by liquid-liquid phase separation

Vendruscolo

Fuxreiter

2020

Preprint

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The transition between the native and amyloid states of proteins can proceed via a deposition pathway through oligomeric intermediates or via a condensation pathway through liquid droplet intermediates generated through liquid-liquid phase separation. The maturation of these droplet intermediates into ordered assemblies has been associated with human disease, including in particular amyotrophic lateral sclerosis (ALS), although the mechanisms of toxicity have not been yet clarified. Here we investigate the processes by which ALS-related mutations give rise to cytotoxicity along the condensation pathway. Based on the sequence-determinants of the different types of interactions stabilising the droplet and amyloid states, we accurately predict the levels of toxicity of about 50,000 deep mutagenesis variants of TDP-43 prion-like domain. We find that condensation is not typically initiated by structural ordering, but rather through non-specific interactions, and that the cytotoxicity of ALS-related TDP-43 mutations stems from promiscuous interactions within the droplet intermediates, rather than from the mature aggregates. These results provide insights into the mechanisms by which condensates convert into amyloids and their links with human disease.SignificanceProtein liquid-liquid phase separation underlies the formation of functional protein condensates, which upon dysregulation can mature into cytotoxic amyloid-containing aggregates. The sequence-based principles governing this pathway, and the mechanisms giving rise to cytotoxicity, however, are still not known in detail. Here, based on the different amino acid codes leading to the droplet and amyloid states, we show how one can predict the toxicity of the intermediate states along the condensation pathway. Our results highlight that this toxicity originates from the interaction promiscuity of amyloid-containing intermediates, in particular those with ALS-related mutations, rather than from the mature amyloid state. These results contribute to our understanding of the mechanisms through which TDP-43 mutations are linked to ALS.

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Head-to-Tail Polymerization in the Assembly of Biomolecular Condensates

Cited by 74 publications

References 111 publications

Diffusion-mediated HEI10 coarsening can explain meiotic crossover positioning in Arabidopsis

Diffusion-mediated HEI10 coarsening can explain meiotic crossover positioning in Arabidopsis

Biomolecular Condensates and Cancer

Sequence determinants of the aggregation of proteins within condensates generated by liquid-liquid phase separation

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