Abstract
Biomolecular condensates formed via liquid–liquid phase separation (LLPS) play a crucial role in the spatiotemporal organization of the cell material. Nucleic acids can act as critical modulators in the stability of these protein condensates. To unveil the role of RNA length in regulating the stability of RNA binding protein (RBP) condensates, we present a multiscale computational strategy that exploits the advantages of a sequence-dependent coarse-grained representation of proteins and a minimal coarse-grained model wherein proteins are described as patchy colloids. We find that for a constant nucleotide/protein ratio, the protein fused in sarcoma (FUS), which can phase separate on its own—i.e., via homotypic interactions—only exhibits a mild dependency on the RNA strand length. In contrast, the 25-repeat proline-arginine peptide (PR25), which does not undergo LLPS on its own at physiological conditions but instead exhibits complex coacervation with RNA—i.e., via heterotypic interactions—shows a strong dependence on the length of the RNA strands. Our minimal patchy particle simulations suggest that the strikingly different effect of RNA length on homotypic LLPS versus RBP–RNA complex coacervation is general. Phase separation is RNA-length dependent whenever the relative contribution of heterotypic interactions sustaining LLPS is comparable or higher than those stemming from protein homotypic interactions. Taken together, our results contribute to illuminate the intricate physicochemical mechanisms that influence the stability of RBP condensates through RNA inclusion.
Highlights
Cells require precise compartmentalization of their material into different organelles in order to function
We compare the effects of RNA-length in the phase behaviour of two different RNAbinding protein (RBP): (1) fused in sarcoma (FUS), which can phase separate on its own at physiological conditions via homotypic protein–protein interactions, and (2) PR25, which only undergoes LLPS at physiological conditions in the presence of RNA (Fig A in the S1 Text) via heterotypic RNA–protein interactions [48, 103, 114]
We find that in condensates sustained by homotypic protein–protein interactions, RNA behaves as a LLPS enhancer that subtly augments the stability of the condensates irrespective of its length, while, in condensates sustained by heterotypic protein–RNA interactions, RNA acts as a LLPS enabler that increases the stability of the condensates in a RNA-length-dependent manner
Summary
Cells require precise compartmentalization of their material into different organelles in order to function. While some of these organelles and compartments are shaped by physical membranes, many others are sustained by a mechanism called liquid–liquid phase separation (LLPS) [1,2,3,4]. Biomolecules including multivalent proteins and, in some cases, nucleic acids, can spontaneously demix into phase-separated droplets known as biomolecular condensates [5, 6]. Sequencedependent molecular simulations can help uncover how specific protein regions, amino acidRNA interactions, or RNA properties influence the experimentally observed behavior [49, 50, 56,57,58]
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