Journal Article

Asymmetric oligomerization state and sequence patterning can tune multiphase condensate miscibility

Rana, Ushnish, Avalos, José L., Xu, Ke, Walls, Mackenzie T., Brangwynne, Clifford P., Narayanan, Amal, Panagiotopoulos, Athanassios Z.

2024

Overview

Endogenous biomolecular condensates, composed of a multitude of proteins and RNAs, can organize into multiphasic structures with compositionally distinct phases. This multiphasic organization is generally understood to be critical for facilitating their proper biological function. However, the biophysical principles driving multiphase formation are not completely understood. Here we use in vivo condensate reconstitution experiments and coarse-grained molecular simulations to investigate how oligomerization and sequence interactions modulate multiphase organization in biomolecular condensates. We demonstrate that increasing the oligomerization state of an intrinsically disordered protein results in enhanced immiscibility and multiphase formation. Interestingly, we find that oligomerization tunes the miscibility of intrinsically disordered proteins in an asymmetric manner, with the effect being more pronounced when the intrinsically disordered protein, exhibiting stronger homotypic interactions, is oligomerized. Our findings suggest that oligomerization is a flexible biophysical mechanism that cells can exploit to tune the internal organization of biomolecular condensates and their associated biological functions. The biomolecular principles underlying the formation of multiphasic condensates have been difficult to elucidate owing to a paucity of tools, especially within living cells. In this work synthetic orthogonal protein scaffolds alongside molecular simulations are used to highlight how the oligomerization of disordered proteins can asymmetrically drive miscibility–immiscibility transitions.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/114/2397 / 631/57/2268 / 631/57/2269 / Amino acid sequence / Analytical Chemistry / Asymmetry / Biochemistry / Biomolecular Condensates - chemistry / Biopolymers in vivo / Chemistry / Chemistry and Materials Science / Chemistry/Food Science / Computational models / Condensates / Immiscibility / In vivo methods and tests / Inorganic Chemistry / INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY / Intrinsically disordered proteins / Intrinsically Disordered Proteins - chemistry / Miscibility / Molecular Dynamics Simulation / Multiphase / Oligomerization / Organic Chemistry / Physical Chemistry / Protein Multimerization / Proteins / RNA - chemistry