Modelling phase separation

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Spatiotemporal control of filamentous protein aggregation - Thomas Michaels - UCL

Biophysical basis of condensate functionality - Jeremy Schmit - Kansas State University

Reentrant liquid condensate phase of proteins mediated by salt - Jerelle Joseph, University of Cambridge

Thursday 8 July 2021
Time: 15:00 BST

Contact: Andela Saric

Spatiotemporal control of filamentous protein aggregation - Thomas Michaels

Abstract: Liquid cellular compartments form in the cyto- or nucleoplasm and can regulate aberrant filamentous protein aggregation. Yet, the mechanisms by which these 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 aggregates strongly partition into the liquid compartment. Aggregate partitioning is caused by a positive feedback mechanism of aggregate nucleation and growth driven by a flux maintaining the phase equilibrium between the compartment and its surrounding. Our model establishes a link between specific aggregating systems and the physical conditions maximizing aggregate partitioning into the compartment. The underlying mechanism of aggregate partitioning could be used to confine cytotoxic protein aggregates inside droplet-like compartments but may also represent a common mechanism to spatially control irreversible chemical reactions in general.

Biography: Dr Thomas Michaels is a newly appointed lecturer in theoretical biophysics at the Department of Physics and Astronomy of UCL. Dr Michaels studied physics and mathematics at ETH Zurich and holds a PhD in Chemistry from the University of Cambridge, where he worked with Tuomas Knowles. Prior to joining UCL, Dr Michaels was a Swiss National Science Foundation postdoctoral fellow in the group of L Mahadevan at Harvard and a Junior Research Fellow in Physics at Peterhouse, University of Cambridge.

Biophysical basis of condensate functionality - Jeremy Schmit

Abstract: Biomolecular condensates are emerging as a common motif for cellular organelles. Due to their liquid properties, it is commonly thought that their utility arises from their role as a compartmentalization mechanism. We have studied two binary mixtures that form liquid condensates, SPOP/DAXX and poly-SUMO/poly-SIM. Using analytic theory to model condensate densities and molecular partitioning, we find that the condensate properties can be explained if the networks stabilizing the condensed phases have dramatically different structures. Furthermore, these structures impart critical functional properties to the resulting network. In the case of SPOP/DAXX condensates the structure allows the network to switch between a fluid state and a gel with arrested dynamics. In contrast, the SUMO/SIM structure provides a sensitive mechanism to recruit client molecules and even specifically select between closely related clients. These findings suggest a general model that functional structure can be embedded within a liquid when the molecules assemble hierarchically via interactions that vary widely in affinity. Stronger interactions provide structural specificity needed for functionality, while weaker interactions allow the molecules to condense without the risk of kinetic arrest.

Biography: Jeremy Schmit uses simple, analytic theories to understand the behavior of systems that contain large numbers of molecules. These systems exhibit complex phenomena, such as aggregation, phase transitions, self-assembly, and viscosity, that cannot be inferred from the properties of individual molecules. Such emergent properties play an important role in cellular organization, neurodegenerative diseases, and the formulation of therapeutic molecules. Prof. Schmit did his undergraduate studies at Northwestern University, a Ph.D. at UC Santa Barbara, and postdocs at Brandeis and UC San Francisco. He has been a faculty member in the Department of Physics at Kansas State University since 2011.

Reentrant liquid condensate phase of proteins mediated by salt - Jerelle Joseph

Abstract:  Many proteins demix into phase-separated compartments under physiological conditions. These biomolecular condensates may play important roles in cellular function and dysfunction. Hence, deciphering the underlying mechanics that govern the formation and dissolution of biomolecular condensates is now an active area of research. Recently, we found that certain cellular proteins (namely, FUS, TDP-43, Brd4, Sox2, and Annexin A11), which are phase-separated at physiological salt, can re-enter the phase-separated regime at high salt. Using advanced fluorescence imaging techniques and multiscale computer simulations, we find that, while low- and high-salt condensates are macroscopically similar, the interactions sustaining condensates in the two salt regimes are fundamentally different. Whereas at low salt both electrostatic and hydrophobic interactions are important, in the high-salt regime hydrophobic and non-ionic forces are the chief drivers of phase separation. This work helps expand our current understanding of how environmental changes can modulate the phase boundaries of proteins, and may also hold important implications for aberrant function and druggabilities of condensates.  Related article:   Krainer*, Welsh*, Joseph* et al. Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions. Nat Commun 12, 1085 (2021).  

Biography:  Jerelle Joseph is from the Commonwealth of Dominica. She obtained a PhD in Chemistry from the University of Cambridge, as a Gates Cambridge Scholar, in the group of Prof David Wales FRS. She is currently a Research Fellow in Physical and Chemical Sciences at King’s College, Cambridge, and works in the lab of Dr Rosana Collepardo-Guevara. Her research focuses on developing multiscale computational approaches to investigate biomolecular phase separation. Beyond her research, Jerelle is the founder of CariScholar; an organisation that connects Caribbean students to mentors in their field of study.


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