Polymer physics of intracellular phase transitions

Journal name:
Nature Physics
Year published:
Published online


Intracellular organelles are either membrane-bound vesicles or membrane-less compartments that are made up of proteins and RNA. These organelles play key biological roles, by compartmentalizing the cell to enable spatiotemporal control of biological reactions. Recent studies suggest that membrane-less intracellular compartments are multicomponent viscous liquid droplets that form via phase separation. Proteins that have an intrinsic tendency for being conformationally heterogeneous seem to be the main drivers of liquid–liquid phase separation in the cell. These findings highlight the relevance of classical concepts from the physics of polymeric phase transitions for understanding the assembly of intracellular membrane-less compartments. However, applying these concepts is challenging, given the heteropolymeric nature of protein sequences, the complex intracellular environment, and non-equilibrium features intrinsic to cells. This provides new opportunities for adapting established theories and for the emergence of new physics.

At a glance


  1. Examples of membrane-less bodies in cells.
    Figure 1: Examples of membrane-less bodies in cells.

    a, P bodies (yellow) in tissue culture cells (adapted from ref. 63, NPG). b, Purinosomes (adapted from ref. 3, AAAS). c, Nucleoli (red) and histone locus bodies (green) in the nucleus of a large X. laevis oocyte (adapted from ref. 14, NPG).

  2. Molecular interactions underlying intracellular phase transitions.
    Figure 2: Molecular interactions underlying intracellular phase transitions.

    The three panels at the top right show the domain architectures for FUS, DDX4 and LAF-1. In each panel, the numbers shown to the right of the domain architecture denote the lengths of the corresponding proteins. The amino acid biases within low-complexity regions of each protein are highlighted in square boxes that show portions of the actual amino acid sequence and annotation of the sequence stretch using symbols to denote dipoles (triangles), charges (+ or −), aromatic groups (circles) and aliphatic groups (squares). For the sequences of DDX4 and LAF-1, the sequence patterning ensures the linear segregation of oppositely charged residues. The panel to the top left shows schematics of the hierarchical modes of interactions that are likely to drive the phase separation of different sequences. This schematic is annotated to depict the types of interactions, their ranges, and their expected salt dependencies. The bottom panel shows schematic representations of micron-sized droplets formed by each of the three proteins. The insets for each droplet depict the dominant interactions that are expected to prevail among molecules that make up the dense liquid. The contours of individual polypeptide backbones are shown in black. In all of the droplets the interactions are likely to involve interplay among electrostatic, dipolar and short-range directional interactions involving aromatic groups.


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Author information


  1. Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey 08544, USA

    • Clifford P. Brangwynne
  2. VIB Structural Biology Research Center (SBRC), Vrije Universiteit Brussel, Brussels 1050, Belgium

    • Peter Tompa
  3. Institute of Enzymology, Research Centre for Natural Sciences of the Hungarian Academy of Sciences, 1117 Budapest, Hungary

    • Peter Tompa
  4. Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St Louis, St Louis, Missouri 63130, USA

    • Rohit V. Pappu

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