Rhomboid distorts lipids to break the viscosity-imposed speed limit of membrane diffusion

Science. 2019 Feb 1;363(6426):eaao0076. doi: 10.1126/science.aao0076.


Enzymes that cut proteins inside membranes regulate diverse cellular events, including cell signaling, homeostasis, and host-pathogen interactions. Adaptations that enable catalysis in this exceptional environment are poorly understood. We visualized single molecules of multiple rhomboid intramembrane proteases and unrelated proteins in living cells (human and Drosophila) and planar lipid bilayers. Notably, only rhomboid proteins were able to diffuse above the Saffman-Delbrück viscosity limit of the membrane. Hydrophobic mismatch with the irregularly shaped rhomboid fold distorted surrounding lipids and propelled rhomboid diffusion. The rate of substrate processing in living cells scaled with rhomboid diffusivity. Thus, intramembrane proteolysis is naturally diffusion-limited, but cells mitigate this constraint by using the rhomboid fold to overcome the "speed limit" of membrane diffusion.

Publication types

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

MeSH terms

  • Animals
  • Cell Membrane / chemistry*
  • Diffusion
  • Drosophila
  • HEK293 Cells
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Lipid Bilayers / chemistry
  • Membrane Proteins / chemistry*
  • Peptide Hydrolases / chemistry*
  • Protein Structure, Tertiary*
  • Proteolysis
  • Single Molecule Imaging
  • Viscosity*


  • Lipid Bilayers
  • Membrane Proteins
  • Peptide Hydrolases