How phase separation organizes the cell

A new review sheds light on the interaction between cell membranes and cell organelles

To maintain order within itself, the cell organizes its building blocks into different regions. Membrane-bound cell organelles such as the nucleus and mitochondria are not the only ones involved in this process. A review by researchers at the Max Planck Institute of Colloids and Interfaces shows how phase separation also contributes to the formation of dynamic structures such as biomolecular condensates and membrane domains.

Cells are densely packed, highly dynamic systems. In a confined space, proteins, nucleic acids, lipids, and numerous other molecules must interact with each other. At the same time, many processes must be spatially separated from one another, or molecules must be specifically concentrated in certain locations. To achieve this, the cell utilizes not only classic, membrane-bound organelles such as the nucleus or mitochondria, but also phase separation.

A recent review by Agustín Mangiarotti and Rumiana Dimova of the Max Planck Institute of Colloids and Interfaces shows how phase separation contributes to spatial organization both within the cell and at cell membranes. The review was published in the journal Nature Reviews Molecular Cell Biology.

Two forms of phase separation

Molecules in cells do not always distribute themselves evenly. Under certain conditions, such as temperature and concentration, they separate into different phases. This is based on the physical principle of phase separation, whereby substances separate into distinct components, much like oil and vinegar separating in a salad dressing. Typically, this results in a denser phase, in which the molecules involved are more tightly packed and interact more strongly with one another, as well as a dilute phase with a lower concentration.

Inside the cell, this phenomenon occurs in three-dimensional space. It can lead to the formation of so-called biomolecular condensates. In this process, for example, proteins and nucleic acids accumulate in droplet-like formations within distinct, membrane-less regions. Many of these condensates have liquid-like properties.

The same sorting process also takes place along the cell membrane. Lipids and proteins organize themselves laterally into different regions of the two-dimensional membrane. These so-called membrane domains, also known as “rafts,” serve as important platforms for signal transduction and other cellular functions.

When membranes and condensates work together

The discovery of these membraneless condensates has revolutionized cell biology. However, it is not yet fully understood how their material properties determine their functions or how their molecular composition can be tuned.

Although phase separation occurs within the cell and at membranes in different spatial dimensions, the two processes cannot be considered entirely separately from one another. This review demonstrates how closely membranes and biomolecular condensates can be coupled.

For example, membranes influence where and under what conditions biomolecular condensates form and what properties they assume. Conversely, condensates alter the properties and organization of membranes. For instance, they can adhere to membranes, alter their structure, or contribute to their deformation.

This mutual interaction plays a key role in various biological processes, such as signal transduction, immune responses, the formation of tight junctions between cells, at synapses, or stress granules "plugging" ruptures in damaged lysosomes to repair them.

Dimova's group has itself helped establish key methods for this field, for example, showing how factors like lipid packing and cholesterol content tune whether a condensate wets, partially wets, or is repelled by a membrane.

The spatial organization of a cell is thus not determined solely by fixed structures. Physical processes such as phase separation and the interactions between different cellular components also contribute to where molecules come together, which structures form, and how these structures perform their functions. Membrane domains and biomolecular condensates form a closely coupled system that contributes to the spatial organization and function of cells.