The Role of Protein Disorder And Self‐Association in the Formation of Cellular Bodies

Abstract

Cellular “bodies”, i.e. organelles that are not enclosed by membranes, are large protein assemblies with liquid‐like properties, but the biophysical basis for their formation is largely unclear. Recent work demonstrated that weak, multivalent protein interactions, resulting in the formation of large higher‐order complexes, can undergo phase separation in vitro and may enable the formation of cellular bodies. The inherent size heterogeneity of higher‐order complexes renders them difficult to characterize biophysically, limiting molecular insight into their biological functions. We report novel mechanisms governing the formation of nuclear SPOP bodies and stress granules in which the self‐association of folded domains into large homo‐oligomers and of long disordered regions play key roles. We have used biophysical, biochemical and cell biological approaches to characterize protein self‐association in vitro, to quantify the size distribution of the resulting higher‐order oligomers, and to relate these to the function of organelles in cells. We explore how the destabilization or rigidification of cellular bodies can lead to cancer and neurodegenerative diseases. We propose that dynamic protein self‐association is a general mechanism underlying the formation of cellular bodies. These may serve as signaling hotspots that can be dynamically turned on or off through their regulated assembly and disassembly.