Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization

The transformation of molecular binding events into cellular decisions is the basis of most biological signal transduction. A fundamental challenge faced by these systems is that protein-ligand chemical affinities alone generally result in poor sensitivity to ligand concentration, endangering the system to error. Here, we examine the lipid-binding pleckstrin homology and Tec homology (PH-TH) module of Bruton’s tyrosine kinase (Btk) Using fluorescence correlation spectroscopy (FCS) and membrane-binding kinetic measurements, we identify a self-contained phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ) sensing mechanism that achieves switch-like sensitivity to PIP 3 levels, surpassing the intrinsic affinity discrimination of PIP 3 :PH binding. This mechanism employs multiple PIP 3 binding as well as dimerization of Btk on the membrane surface. Mutational studies in live cells confirm that this mechanism is critical for activation of Btk in vivo . These results demonstrate how a single protein module can institute a minimalist coincidence detection mechanism to achieve high-precision discrimination of ligand concentration.