Avidity-driven polarity establishment via multivalent lipid-GTPase module interactions

EMBO J. 2019 Feb 1;38(3):e99652. doi: 10.15252/embj.201899652. Epub 2018 Dec 17.


While Rho GTPases are indispensible regulators of cellular polarity, the mechanisms underlying their anisotropic activation at membranes have been elusive. Using the budding yeast Cdc42 GTPase module, which includes a guanine nucleotide exchange factor (GEF) Cdc24 and the scaffold Bem1, we find that avidity generated via multivalent anionic lipid interactions is a critical mechanistic constituent of polarity establishment. We identify basic cluster (BC) motifs in Bem1 that drive the interaction of the scaffold-GEF complex with anionic lipids at the cell pole. This interaction appears to influence lipid acyl chain ordering, thus regulating membrane rigidity and feedback between Cdc42 and the membrane environment. Sequential mutation of the Bem1 BC motifs, PX domain, and the PH domain of Cdc24 lead to a progressive loss of cellular polarity stemming from defective Cdc42 nanoclustering on the plasma membrane and perturbed signaling. Our work demonstrates the importance of avidity via multivalent anionic lipid interactions in the spatial control of GTPase activation.

Keywords: Rho GTPase; cell polarity; lipids; nanoclustering; super‐resolution imaging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Membrane / metabolism*
  • Cell Polarity*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Phosphatidylinositols / metabolism*
  • Phosphatidylserines / metabolism*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Signal Transduction


  • Adaptor Proteins, Signal Transducing
  • CDC24 protein, S cerevisiae
  • Cell Cycle Proteins
  • Guanine Nucleotide Exchange Factors
  • Phosphatidylinositols
  • Phosphatidylserines
  • Saccharomyces cerevisiae Proteins
  • BEM1 protein, S cerevisiae