Ultrasensitivity in multisite phosphorylation of membrane-anchored proteins

Biophys J. 2011 Mar 2;100(5):1189-97. doi: 10.1016/j.bpj.2011.01.060.


Cellular signaling is initially confined to the plasma membrane, where the cytoplasmic tails of surface receptors and other membrane-anchored proteins are phosphorylated in response to ligand binding. These proteins often contain multiple phosphorylation sites that are regulated by membrane-confined enzymes. Phosphorylation of these proteins is thought to be tightly regulated, because they initiate and regulate signaling cascades leading to cellular activation, yet how their phosphorylation is regulated is poorly understood. Ultrasensitive or switchlike responses in their phosphorylation state are not expected because the modifying enzymes are in excess. Here, we describe a novel mechanism of ultrasensitivity exhibited by multisite membrane-anchored proteins, but not cytosolic proteins, even when enzymes are in excess. The mechanism underlying this concentration-independent ultrasensitivity is the local saturation of a single enzyme by multiple sites on the substrate. Local saturation is a passive process arising from slow membrane diffusion, steric hindrances, and multiple sites, and therefore may be widely applicable. Critical to this ultrasensitivity is the brief enzymatic inactivation that follows substrate modification. Computations are presented using ordinary differential equations and stochastic spatial simulations. We propose a new role, to our knowledge, for multisite membrane-anchored proteins, discuss experiments that can be used to probe the model, and relate our findings to previous theoretical work.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Membrane / metabolism
  • Diffusion
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism*
  • Models, Biological*
  • Phosphoproteins / chemistry*
  • Phosphoproteins / metabolism*
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphorylation
  • Phosphotransferases / metabolism


  • Membrane Proteins
  • Phosphoproteins
  • Phosphotransferases
  • Phosphoric Monoester Hydrolases