Reentrant liquid condensate phase of proteins is stabilized by

hydrophobic and non-ionic interactions

A multidisciplinary team from the University of Cambridge and other leading research institutions around the globe unravel the forces behind reentrant protein condensation and discuss the implications in the development of therapies targeting neurodegenerative diseases and cancer.

The cell interior contains a myriad of different proteins and other biomolecules that need to be carefully catalogued for the cell to function correctly. Apart from the nucleus and other well-known membrane-enclosed cellular structures, many intracellular compartments are actually membraneless. These so-called biomolecular condensates are protein-rich liquid drops that remain segregated in space simply by the physics of phase separation – analogous to the separation of oil and water into distinct liquid phases. Liquid–liquid phase separation confers a huge advantage to these compartments, over their membrane-bound analogues: the cell can dynamically trigger their formation and dissolution on demand by changing its environment (i.e., temperature, pH, etc.), in order to rapidly carry out functions relating to cell stress, gene regulation, and many other processes. In a recent paper published in Nature Communications, a team of researchers investigate how changes in salt concentration transform the way proteins interact with one another, making condensates stable or triggering their dissolution.

“Surprisingly”, says Dr Georg Krainer, co-first author of this paper and Research Fellow in the group of Prof. Tuomas Knowles, “we find that several proteins can form condensates under both low and high salt conditions thereby exhibiting a reentrant phase separation behaviour.” The authors show that the molecular interactions driving the phase transition in the low- and high-salt regime are fundamentally different. Whereas hydrophobic and electrostatic interactions are both important at low salt, in the high salt regime the condensate compartments are sustained predominantly by hydrophobic and non-ionic interactions. 

Timothy Welsh, co-first author and graduate student in the Knowles laboratory, stresses the importance of working in a multidisciplinary team and asserts: “This project would not have been possible without the strong collaboration between experimentalists and computational scientists”.

The findings published by Krainer, Welsh, Joseph et al. will have important implications in the field of neurodegenerative disease and cancer. The ability of different types of interactions to act as nonspecific modulators of protein phase separation has important implications for how we develop therapies for aberrant condensates, such protein aggregation observed in diseases like Parkinson’s and Alzheimer’s disease. 

Dr Jerelle Joseph, co-first author and Research Fellow in the group of Dr Rosana Collepardo, adds, “our study suggests that in the origin of life the high salt concentrations of oceans could have facilitated the formation of protocells via protein phase separation; essentially keepingselected biomolecules concentrated.”

The work is a collaboration between the Knowles Lab (University of Cambridge), the Collepardo Lab (University of Cambridge), the Alberti Lab (TU Dresden), the Hyman Lab (Max Planck Institute of Molecular Cell Biology and Genetics), and the St George-Hyslop Lab (University of Cambridge and University of Toronto).

Reference: Krainer, G., Welsh, T. J., Joseph, J.A. et al. “Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions”. Nat. Commun. 12, 1085 (2021). https://doi.org/10.1038/s41467-021-21181-9