RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins

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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.
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Funding Information
  • H2020 European Research Council (803326)
  • Oppenheimer Fellowship
  • Roger Ekins Fellowship
  • Oppenheimer Fellowship
  • Engineering and Physical Sciences Research Council (EP/T517847/1)
  • Derek Brewer Emmanuel College scholarship
  • Engineering and Physical Sciences Research Council (EP/P020259/1)
  • Engineering and Physical Sciences Research Council (EP/P020259/1)
  • Engineering and Physical Sciences Research Council (EP/P020259/1)
  • Engineering and Physical Sciences Research Council (EP/P020259/1)

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