Oligomerization and sequence patterning can tune multiphasic condensate miscibility.

Abstract

Endogenous biological condensates, comprised of a multitude of proteins and RNAs, are organized into multiphasic structures. This multiphasic organization is generally understood to be critical for facilitating the proper biological function of these condensates. However, the biophysical principles driving multiphase formation are poorly understood. Here, we utilize in vivo experiments and coarse-grained molecular simulations to investigate how oligomerization and sequence interactions modulate multiphase organization in biological condensates. We demonstrate that increasing the oligomerization state of an IDR results in enhanced immiscibility and multiphase formation. Strikingly, we found that oligomerization can asymmetrically tune the miscibility of IDRs, with the effect being more potent when applied to stronger homotypic IDRs. Finally, we utilized the nucleolus as a model multiphasic condensate to demonstrate how perturbing the oligomerization of nucleolar components in the granular component can change their localization to the nucleolar periphery. Our findings lead us to propose oligomerization as a flexible biophysical mechanism which cells can exploit to tune the multiphasic organization of biological condensates and thereby regulate their biological function.