Exploring the Role of Liquid-Liquid Phase Separation in Cellular Functions

Organising Cellular Functions: The Role of Organelles

Cells are master organisers, utilising various compartments to manage their myriad functions. Classic examples include mitochondria, which supply the cell with energy; the nucleus, which stores and protects sensitive DNA; and lysosomes, which compartmentalise the harsh chemistry required to break down unwanted molecules. To help keep things organised, most organelles are wrapped in a lipid membrane, providing a physical barrier.

However, there is also a class of organelles that lack a membrane. These are often smaller, specialised to certain cell types or conditions, and tend to form and disappear as needed. The nature and function of these membraneless organelles have been more difficult to pin down, but recent years have brought significant insights about them.

Membraneless Organelles: Formed Through Phase Separation

In 2009, Brangwynne and coworkers published a report describing the dynamics of p-bodies, a type of membraneless organelle associated with the differentiation of germ-line cells. The study revealed that these granules behaved much like liquid droplets, capable of fusing and splitting, deforming under stress, and possessing a fully fluid interior. The droplets would form or dissolve depending on external stimuli, revealing an elegant means of cellular organisation.

Following this discovery, a growing number of other organelles have been revealed to be liquid condensates. Many of these structures contain a mixture of RNA and proteins and play important roles in gene expression, regulation of cell division, and transport and protection of RNA.

These condensates form through a process called liquid-liquid phase separation (LLPS). This general phenomenon occurs when two liquids demix, forming droplets of one liquid phase suspended in the other. In biology, LLPS is typically driven by interactions between proteins and other macromolecules, promoting the formation of a protein-enriched dense phase. For a more in-depth discussion of LLPS, please refer to our post on the matter.

A Growing Field of Research

Given the importance of biomolecular condensates in so many critical cellular processes, there has been a surge in research to explore their function and the underlying mechanisms that guide their assembly. This has created an emerging field that brings together researchers from diverse backgrounds. While the relevant context is deeply rooted in cell biology and biochemistry, methods and concepts from biophysics are becoming increasingly important to map out the thermodynamics and driving forces. Additional insights come from the fields of polymer physics and colloidal chemistry, where liquid-liquid phase separation has a long-standing history.

Future Directions: What’s Next?

The exploration of biomolecular condensates and phase separation is quickly expanding our understanding of how cells function and how these functions can be disrupted. Since phase separation has been shown to play a key role in the regulation of gene expression and cell division, it seems plausible that misregulation of phase separation is involved in the unchecked proliferation of cancer cells. Driven by this insight, several research groups are now pursuing ways to leverage the growing knowledge about biomolecular condensates to develop new forms of cancer diagnosis and treatment.

Several proteins implicated in neurodegenerative diseases, such as ALS and Parkinson’s disease, have also been found to form condensates. In many cases, there seems to be an interplay between liquid condensates and the formation of the solid aggregates typically linked to disease. A better understanding of the phase behaviour of key proteins and how they are altered in disease could greatly benefit the neurodegeneration field.

The insights gained from studying how nature uses condensates to optimise and regulate reactions could also be applied in biotechnology and synthetic biology. For example, green chemistry could be enhanced with artificial compartments designed to sequester enzymes and reagents, releasing products in a controlled manner.

Conclusion: The Importance of LLPS

Liquid-liquid phase separation (LLPS) and its role in cellular function is a fascinating and rapidly growing field of research. The potential connection between LLPS and diseases such as cancer and neurodegenerative disorders makes it a crucial area of study. Furthermore, the potential applications of LLPS in areas like green chemistry and synthetic biology could lead to breakthroughs in sustainability and bioengineering. Therefore, whether you are a scientist, a student, or a curious individual, understanding LLPS and its implications is not only intriguing but could also be vital for the future of medicine and bioengineering.