ATP Mediates Phase Separation of Disordered Basic Proteins by Bridging Intermolecular Interaction Networks

Kota, Divya; Prasad, Ramesh; Zhou, Huan-Xiang

doi:10.1101/2023.08.20.554035

Cited by 5 publications

(15 citation statements)

References 43 publications

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“…Thus, the viscocapillary model seems to be a reasonable choice for estimating the surface tension of condensates formed by fully disordered proteins but not necessarily for those involving folded domains. However, given that the spatiotemporal evolution of condensates is only beginning to be explored, we advise caution in inferring the surface tension of condensates through indirect measurements via the viscocapillary model, particularly when environmental variables such as salt and ATP 99 play a role in regulating the thermodynamics and dynamics of biomolecular condensates.…”

Section: Methodsmentioning

confidence: 99%

Sequence-Dependent Material Properties of Biomolecular Condensates and their Relation to Dilute Phase Conformations

Devarajan

Wang

Nikoubashman

et al. 2023

Preprint

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Material properties of phase-separated biomolecular assemblies, enriched with disordered proteins, dictate their ability to participate in many cellular functions. Despite the significant effort dedicated to understanding how the sequence of the disordered protein drives its phase separation to form condensates, little is known about the sequence determinants of condensate material properties. Here, we decipher these relationships for charged disordered proteins using model sequences comprised of glutamic acid and lysine residues as well as naturally occurring sequences of LAF1's RGG domain and DDX4's N-terminal domain. We do so by delineating how the arrangement of oppositely charged residues within these sequences influences the dynamical, rheological, and interfacial properties of the condensed phase. Interestingly, we find that the material properties of both the model and natural proteins respond similarly to the segregation of charges, despite their very different sequence compositions. Condensates of the highly charge-segregated sequences exhibit slower dynamics than the uniformly charge-patterned sequences, because of their comparatively long-lived molecular contacts between oppositely charged residues. Surprisingly, the molecular interactions within the condensate are highly similar to those within a single-chain for all sequences. Consequently, the condensate material properties of charged disordered proteins are strongly correlated with their dense-phase contact dynamics and their single-chain structural properties. Our findings demonstrate the potential to harness the sequence characteristics of disordered proteins for engineering the material properties of functional condensates, with insights from the dilute-phase properties.

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Section: Methodsmentioning

confidence: 99%

Sequence-Dependent Material Properties of Biomolecular Condensates and their Relation to Dilute Phase Conformations

Devarajan

Wang

Nikoubashman

et al. 2023

Preprint

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“…In addition to charge neutralization, we suspected that ions could also fortify intermolecular interactions by bridging between proteins, similar to the role played by ATP molecules in driving phase separation of positively charged IDPs. 28 Indeed, we found that Clhas a tendency to bind with Arg and other sidechains from multiple chains and likewise, Na + has a tendency to bind with backbone carbonyls and sidechain oxygens from multiple chains (Figure 4A).…”

Section: Ions Act As Bridges Between Protein Chains To Drive Condensa...mentioning

confidence: 85%

“…2 For example, these simulations showed that ATP, a small molecule with a -4 charge, bridges between positively charged IDP chains in driving phase separation. 28 The intermolecular interactions quickly break and reform, explaining why the condensates can rapidly fuse despite very high macroscopic viscosity. Similarly, quick breakup and reformation of salt bridges in a heterotypic condensate allow the protein molecules to be extremely dynamic in a highly viscous environment.…”

Section: Introductionmentioning

confidence: 99%

Direct and Indirect Salt Effects on Homotypic Phase Separation

MacAinsh,

Dey,

Zhou

2024

Preprint

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The low-complexity domain of hnRNPA1 (A1-LCD) phase separates in a salt-dependent manner. Unlike many intrinsically disordered proteins (IDPs) whose phase separation is suppressed by increasing salt concentrations, the phase separation of A1-LCD is promoted by > 100 mM NaCl. To investigate the atypical salt effect on A1-LCD phase separation, we carried out all-atom molecular dynamics simulations of systems comprising multiple A1-LCD chains at NaCl concentrations from 50 to 1000 mM NaCl. The ions occupy first-shell as well as more distant sites around the IDP chains, with Arg sidechains and backbone carbonyls the favored partners of Cl- and Na+, respectively. They play two direct roles in driving A1-LCD condensation. The first is to neutralize the high net charge of the protein (+9) by an excess of bound Cl- over Na+; the second is to bridge between A1-LCD chains, thereby fortifying the intermolecular interaction networks in the dense phase. At high concentrations, NaCl also indirectly strengthens π-π, cation-π, and amino-π interactions, by drawing water away from the interaction partners. Therefore, at low salt, A1-LCD is prevented from phase separation by net charge repulsion; at intermediate concentrations, NaCl neutralizes enough of the net charge while also bridging IDP chains to drive phase separation. This drive becomes even stronger at high salt. Based on this understanding, four salt effect types on the phase separation of IDPs can be predicted based on their amino-acid compositions.

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“…They observed slab formation in the simulations. Kota et al 135 used SpiDecbased all-atom simulations to characterize the condensate formed by mixing a small basic IDP (bIDP) called protamine with ATP. In neither of these last two studies the solute molecules in the dense slab exchanged with the dilute phase in the available simulation time.…”

Section: Levels Of Representation Of Biomolecular Systems In Simulationsmentioning

confidence: 99%

Fundamental Aspects of Phase-Separated Biomolecular Condensates

Zhou,

Kota,

Qin

et al. 2024

Chem. Rev.

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Biomolecular condensates, formed through phase separation, are upending our understanding in much of molecular, cell, and developmental biology. There is an urgent need to elucidate the physicochemical foundations of the behaviors and properties of biomolecular condensates. Here we aim to fill this need by writing a comprehensive, critical, and accessible review on the fundamental aspects of phase-separated biomolecular condensates. We introduce the relevant theoretical background, present the theoretical basis for the computation and experimental measurement of condensate properties, and give mechanistic interpretations of condensate behaviors and properties in terms of interactions at the molecular and residue levels.

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ATP Mediates Phase Separation of Disordered Basic Proteins by Bridging Intermolecular Interaction Networks

Cited by 5 publications

References 43 publications

Sequence-Dependent Material Properties of Biomolecular Condensates and their Relation to Dilute Phase Conformations

Sequence-Dependent Material Properties of Biomolecular Condensates and their Relation to Dilute Phase Conformations

Direct and Indirect Salt Effects on Homotypic Phase Separation

Fundamental Aspects of Phase-Separated Biomolecular Condensates

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