Phase transitions in the assembly of multivalent signalling proteins

Nature. 2012 Mar 7;483(7389):336-40. doi: 10.1038/nature10879.


Cells are organized on length scales ranging from ångström to micrometres. However, the mechanisms by which ångström-scale molecular properties are translated to micrometre-scale macroscopic properties are not well understood. Here we show that interactions between diverse synthetic, multivalent macromolecules (including multi-domain proteins and RNA) produce sharp liquid-liquid-demixing phase separations, generating micrometre-sized liquid droplets in aqueous solution. This macroscopic transition corresponds to a molecular transition between small complexes and large, dynamic supramolecular polymers. The concentrations needed for phase transition are directly related to the valency of the interacting species. In the case of the actin-regulatory protein called neural Wiskott-Aldrich syndrome protein (N-WASP) interacting with its established biological partners NCK and phosphorylated nephrin, the phase transition corresponds to a sharp increase in activity towards an actin nucleation factor, the Arp2/3 complex. The transition is governed by the degree of phosphorylation of nephrin, explaining how this property of the system can be controlled to regulatory effect by kinases. The widespread occurrence of multivalent systems suggests that phase transitions may be used to spatially organize and biochemically regulate information throughout biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actin-Related Protein 2-3 Complex / metabolism
  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism
  • Binding Sites
  • Biopolymers / chemistry
  • Biopolymers / metabolism
  • Fluorescence Recovery After Photobleaching
  • HeLa Cells
  • Humans
  • Ligands
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / metabolism*
  • Oncogene Proteins / chemistry
  • Oncogene Proteins / metabolism
  • Phase Transition*
  • Phosphorylation
  • Proline-Rich Protein Domains
  • Protein Structure, Quaternary
  • Proteins / chemistry*
  • Proteins / metabolism*
  • Signal Transduction*
  • Wiskott-Aldrich Syndrome Protein, Neuronal / chemistry
  • Wiskott-Aldrich Syndrome Protein, Neuronal / metabolism
  • src Homology Domains


  • Actin-Related Protein 2-3 Complex
  • Adaptor Proteins, Signal Transducing
  • Biopolymers
  • Ligands
  • Membrane Proteins
  • Multiprotein Complexes
  • Nck protein
  • Oncogene Proteins
  • Proteins
  • Wiskott-Aldrich Syndrome Protein, Neuronal
  • nephrin