Study suggests proteins can compartmentalize and form droplets inside cells

In physics, a system composed of two substances can be modeled according to classical mixture theory, which considers the fraction corresponding to each constituent and the interactions between the constituents. Examples include the coexistence of high and low density phases in supercooled water and the coexistence of metal puddles in an insulating matrix in the Mott metal-insulator transition.

Motivated by this type of consideration, researchers at São Paulo State University (UNESP) in Rio Claro, Brazil, used concepts from condensed matter physics to describe the compartmentalization of proteins in cells and have proposed a Griffiths-type cell phase in direct analogy with the canonical magnetic Griffiths. phase.

The study is published in the journal Heliyon. The last author and principal investigator is Mariano de Souza, professor at the Institute of Geosciences and Exact Sciences (IGCE-UNESP), and the first author is Lucas Squillante, a Ph.D. candidate at the same university.

“In the Griffiths magnetic phase, magnetized or non-magnetized regions emerge in paramagnetic or ferromagnetic matrices, respectively, resulting in a significant reduction in the dynamics of the systems. These “rare regions” emerge randomly. In previous work, we explored the Griffiths-type electronic phase, at the limit of the metal-insulator Mott transition, in this study we focused on protein droplets formed inside cells as “rare regions”, in direct analogy to the Griffiths magnetic phase,” Souza said.

Protein production within a cell can reach a threshold that gives rise to liquid-liquid phase separation and compartmentalization of proteins into droplets. “Using thermodynamic tools such as the Grüneisen parameter, the Flory-Huggins model and the Avramov-Casalini model, we show that cellular dynamics are significantly reduced in the vicinity of the binodal line that determines phase separation, and also for an equivalent protein/solvent ratio, giving rise to a Griffiths-like cell phase,” Souza said.

The study also proposes that the Griffiths-like cell phase is associated with the origin of life and the emergence of primordial organisms, consistent with the classical theory formulated by Russian biologist and biochemist Aleksandr Oparin (1894-1980) in the 1930s, since only coacervates (droplets of organic molecules grouped together in an aqueous solution) with slow dynamics survived and evolved.

“This in turn could be linked to the fundamental role played by homochirality in the evolution of life,” Souza said. Chirality is the property of an object or molecule that means it cannot be superimposed on its image in a mirror. Human hands are chiral, for example. Homochirality is the predominance of a single chirality in the molecules of a biological system.

The researchers demonstrate in the study that an increase in protein diffusion time occurs concomitantly with a reduction in stochastic fluctuations in the cell, which is essential for optimizing gene expression. The study provides an alternative approach to study the dynamics of protein compartmentalization, which could also be applied to 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, particularly with regard to tumorigenesis. The idea is that proteins encoded by genes associated with “such diseases can be compartmentalized and this affects their role in cellular mutation,” said Marcos Minicucci, professor of clinical medicine at UNESP Botucatu and co-author of the article.

Other examples of the role phase separation plays include cataracts (where phase separation in the retina can cause visual impairment), neurodegenerative diseases, and even COVID-19 (where coacervation of the SARS N protein -CoV-2 can suppress the innate immune response to the virus). It was recently reported that phase separation associated with ferroptosis suppressing protein 1 (FSP1) could be used in effective therapeutic intervention against cancer.

“Liquid-liquid phase separation affects each disease differently, and the formation of protein droplets may or may not be beneficial. The Griffiths-like cell phase we propose may have a significant impact on disease management and even treatment.” , Minicucci said. The study conducted by de Souza’s group demonstrates the importance of interdisciplinarity in basic science projects.

Other co-authors besides Squillante, Minicucci and Souza are Antonio Seridonio (UNESP Ilha Solteira), Roberto Lagos-Monaco (UNESP Rio Claro), Aniekan Magnus Ukpong (University of KwaZulu-Natal, Pietermaritzburg, South Africa), Luciano Ricco ( University of Iceland) and Isys Mello, a Ph.D. candidate supervised by Souza.