Polyamines promote disordered protein phase separation

Abstact Membrane-less organelles are spatially heterogenous deposits of interacting macromolecules, often intrinsically disordered proteins and RNA, that form and dissolve in response to cellular stimuli. How membraneless organelles control composition while maintaining stimuli-responsiveness in an environment with competitive interactions is not well understood. Here we demonstrate that natural polyamines, which are found in all living organisms and help in many biological processes, promote protein phase separation via attractive interactions with acidic disordered domains. We show that the abundant polyamine spermine promotes phase separation of the stress-granule associated protein G3BP1 and modulates together with RNA the phase separation and amyloid formation of the Parkinson’s disease-related protein α-synuclein. Polyamine-promoted phase separation is controllable via polyamine acetylation and RNA-mediated competitive interactions. The results suggest that cellular polyamines may serve diverse roles in biomolecular condensation and the regulation of membraneless organelles.