Soiree

Liquid-liquid phase separation in cells

Spatial control of irreversible protein aggregation

Dr Christoph Weber

Max Planck Institute, Dresden

Physical determinants of liquid-liquid phase separation of proteins mixtures

Dr Jorge Rene-Espinosa

Maxwell Centre, University of Cambridge

Thursday 28th March 2019
Time: 4pm
Venue: Room G20, Royal School of Mines, Imperial College London
Contact: Ms Hafiza Bibi
Tel: 020 7594 7252

Spatial control of irreversible protein aggregation

Dr Christoph Weber

Liquid cellular compartments spatially segregate from the cytoplasm and can regulate aberrant protein aggregation, a process linked to several medical conditions, including Alzheimer's and Parkinson's diseases. Yet the mechanisms by which these droplet-like compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid compartments. We find that, even for weak interactions between the compartment constituents and the aggregating monomers, aggregates are strongly enriched inside the liquid compartment relative to the surrounding cytoplasm. We show that this enrichment is caused by a positive feedback mechanism of aggregate nucleation and growth which is mediated by a flux maintaining the phase equilibrium between the compartment and the cytoplasm. Our model predicts that the compartment volume that maximizes aggregate enrichment in the compartment is determined by the reaction orders of aggregate nucleation. The underlying mechanism of aggregate enrichment could be used to confine cytotoxic protein aggregates inside droplet-like compartments suggesting potential new avenues against aberrant protein aggregation. Our findings could also represent a common mechanism for the spatial control of irreversible chemical reactions in general.

Biography: Christoph A. Weber (Max Planck Institute for the Physics of Complex Systems) studied physics at the Ludwig Maximilian university in Munich and completed his PhD in the group of Erwin Frey about actively propelled particle systems. Then he joined the Max Planck Institute for the Physics of Complex Systems in Dresden as a postdoc and worked together with Frank Jülicher and Anthony Hyman on the physics underlying the spatial-temporal organization of non-membrane bound organelles. Then he investigated active poroelastic materials and the kinetics of protein aggregation in the group of L. Mahadevan at Harvard University. In 2018, he returned back to Dresden as a research group leader joining the Max Planck Institute for the Physics of Complex Systems and the Center for Systems Biology. His group “Mesoscopic Physics of Life” is interested in non-equilibrium phase transitions in living systems, aims to understand the biological function of protein aggregates and protein phases in cells, and how a minimal set of inanimate molecules could have formed life-like assemblies at the origin of life.

 

Physical determinants of liquid-liquid phase separation of proteins mixtures

Dr Jorge Rene-Espinosa

The cell interior contains heterogenous mixtures of thousands of different components that need to be organized in space to facilitate control of function. Such organization is achieved through the formation of organelles that are enclosed by physical membranes and membraneless cellular bodies that are sustained by the physical chemistry of Liquid-Liquid Phase Separation (LLPS). Cellular bodies are liquid-like domains that emerge spontaneoulsy above a critical concentration in mixtures of interacting multivalent proteins and nucleic-acids. Here we uncover the physical determinants that explain control of composition and stability of phase-separated cellular bodies formed by mixtures of proteins with different valencies, topologies, and interaction energies. By combining the well-established physics of self-assembly of colloidal patchy particles with a novel continuous potential optimized for fast and scalable molecular dynamics simulations, we show that when proteins mixtures undergo LLPS, the resulting coexisting phases exhibit  inhomogeneous compositions. We demonstrate that the probability of a given protein to concentrate in the condensed versus the diluted liquid phase in a multi-component mixture correlates with the critical temperature for LLPS of the pure single-component protein system.
We determine that the critical temperature of a single-component protein solution and, in consequence,
the expected concentration of such protein in a condensed multi-component cellular body, increase with the valency of the protein, promiscuous rather than selective binding, stronger protein-protein interaction energies, and distributions of binding sites that do not disfavour formation of a percolating network. Our results show a general mechanisms by which cells can easily control the stability and composition of their liquid-liquid coexisting phases: proteins that concentrate in the condensed phase can decrease more significantly their enthalpic contribution to the free energy of the system via their strong protein-protein interactions, while proteins that concentrate in the diluted phase cannot compete with their higher valency partners and instead are segregated to the diluted phase where their proteinprotein interactions are minimized and their entropy maximised

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