Phase separation in biology and disease-a symposium report

Abstract

Phase separation of multivalent protein and RNA molecules enables cells the formation of reversible nonstoichiometric, membraneless assemblies. These assemblies, referred to as biomolecular condensates, help with the spatial organization and compartmentalization of cellular matter. Each biomolecular condensate is defined by a distinct macromolecular composition. Distinct condensates have distinct preferential locations within cells, and they are associated with distinct biological functions, including DNA replication, RNA metabolism, signal transduction, synaptic transmission, and stress response. Several proteins found in biomolecular condensates have also been implicated in disease, including Huntington's disease, amyotrophic lateral sclerosis, and several types of cancer. Disease-associated mutations in these proteins have been found to affect the material properties of condensates as well as the driving forces for phase separation. Understanding the intrinsic and extrinsic forces driving the formation and dissolution of biomolecular condensates via spontaneous and driven phase separation is an important step in understanding the processes associated with biological regulation in health and disease.

Keywords: biomolecular condensates; granules; membraneless organelles; phase diagram; phase separation; protein disorder.

Figure 1:

Liquid–liquid phase separation is the mechanism by which membrane-less organelles form. Some RNA-binding proteins with intrinsically disordered domains can undergo spontaneous LLPS in vitro. Fawzi and coworkers have shown that phase separation of the RNA-binding protein hnRNPA2 is altered by disease mutations, post-translational modifications, and protein–protein interactions. The image is a micrograph of hnRNPA2 low-complexity domain phase separation in the presence of salt and low temperature; hnRNPA2 and TDP-43 proteins aggregate together (in a test tube), providing a possible model for probing the structural details of their aggregation in neurodegenerative disease. Image credit: Veronica H. Ryan, Brown University.