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

Ignacio Sanchez-Burgos, Jorge R. Espinosa, Jerelle A. Joseph, Rosana Collepardo-Guevara

Research output: Contribution to journalArticlepeer-review

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. Here, we present a multiscale computational strategy, exploiting the advantages of both a sequence-dependent coarse-grained representation of proteins and a minimal coarse-grained model that describes proteins as patchy colloids, to unveil the role of RNA length in regulating the stability of RNA-binding protein (RBP) condensates. We find that for a constant nucleotide/protein ratio at which phase separation is enhanced, 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, where we recapitulate the modulation of homotypic protein LLPS and complex coacervation by RNA length, suggest that the strikingly different effect of RNA length on homotypic LLPS versus complex coacervation is general. Phase separation is RNA-length dependent as long as the relative contribution of heterotypic interactions sustaining LLPS is comparable or higher than that 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.

Original languageEnglish (US)
Article numbere1009810
JournalPLoS computational biology
Volume18
Issue number2
DOIs
StatePublished - Feb 2022
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Ecology, Evolution, Behavior and Systematics
  • Cellular and Molecular Neuroscience
  • Molecular Biology
  • Ecology
  • Computational Theory and Mathematics
  • Modeling and Simulation

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