Unveiling a New Cellular Phase for Protein Compartmentalization

Classical mixture theory, which considers both the proportion of each constituent and the interactions between them, can be used to model a physical system composed of two substances.

Two examples are the coexistence of metal puddles in an insulating matrix during the Mott metal-insulator transition and the coexistence of high- and low-density phases in supercooled water.

Inspired by this type of thought, scientists at São Paulo State University (UNESP) in Rio Claro, Brazil, proposed a cellular Griffiths-like phase that is a direct analog of the canonical magnetic Griffiths phase. They did this by using ideas from condensed matter physics to explain protein compartmentalization in cells.

The study Was published in the journal Heliyon. Lucas Squillante, a PhD candidate at the same university, is the first author, and Mariano de Souza, a Professor at the Institute of Geosciences and Exact Sciences (IGCE-UNESP), is the Last Author And Principal Investigator.

In the magnetic Griffiths phase, magnetized or non-magnetized regions emerge in paramagnetic or ferromagnetic matrices respectively, giving rise to a significant reduction in the dynamics of the systems. These so-called ‘rare regions’ emerge randomly. In previous work, we explored the electronic Griffiths-like phase at the verge of the Mott metal-insulator transition. In this study, we focused on the protein droplets formed inside cells as ‘rare regions’, in direct analogy with the magnetic Griffiths phase.”

Mariano de Souza, Professor, Institute of Geosciences and Exact Sciences, São Paulo State University

Proteins can compartmentalize into droplets and separate into liquid-liquid phases when the amount of protein produced inside a cell reaches a certain threshold.

Using thermodynamics tools such as the Grüneisen parameter, the Flory-Huggins model, and the Avramov-Casalini model, we show that cellular dynamics is dramatically reduced in the vicinity of the binodal line that determines phase separation, and also for an equivalent protein/solvent concentration, giving rise to a Griffiths-like cellular phase.”

Mariano de Souza, Professor, Institute of Geosciences and Exact Sciences, São Paulo State University

Only coacervates (droplets of organic molecules clustering in an aqueous solution) with slow dynamics survived and evolved. The study also suggests that the Griffiths-like cellular phase is linked to the beginning of life and the emergence of primordial organisms, in line with the classical theory developed by Russian biologist and biochemist Aleksandr Oparin (1894-1980) in the 1930s.

“This in turn may be linked to the fundamental role played by homochirality in the evolution of life,” Souza said.

An object or molecule is said to be chiral if it cannot be overlaid on its mirror image. For instance, human hands are chiral. When a single chirality predominates in molecules within a biological system, this is known as homochirality.

In the study, the researchers show that a decrease in stochastic fluctuations within the cell is correlated with an increase in protein diffusion time, which is crucial for maximizing gene expression. The study provides a different method for examining protein compartmentalization dynamics, which might potentially be useful in other biological systems.

The fundamental role played by liquid-liquid phase separation in the development and treatment of diseases is widely discussed in the literature, especially about tumorigenesis. The idea is that proteins encoded by genes associated with such diseases can be compartmentalized and that this affects their role in cell mutation.”

Marcos Minicucci, Professor and Study Co-Author, Clinical Medicine, São Paulo State University

Additional instances of the function of phase separation include neurodegenerative illnesses, cataracts (where visual impairment can result from phase separation in the retina), and even COVID-19 (where coacervation of the SARS-CoV-2 N protein can decrease the innate immune response to the virus).

According to a recent investigation, ferroptosis-suppressing protein 1 (FSP1)-related phase separation can be employed as a successful cancer treatment.

“Liquid-liquid phase separation affects each disease differently, and protein droplet formation may or may not be beneficial. The Griffiths-like cellular phase we are proposing can have a significant impact in managing and even treating diseases,” Minicucci said.

Souza's group's study highlights the value of interdisciplinary research in basic science undertakings.