Conformational Control of the Ste5 Scaffold Protein Insulates Against MAP Kinase Misactivation.
*These authors contributed equally to this work.
Cells reuse signaling proteins in multiple pathways, raising the potential for improper crosstalk. Scaffold proteins are thought to insulate against such miscommunication by sequestering proteins into distinct physical complexes. We show that the scaffold protein Ste5, which organizes the yeast mating mitogen-activated protein (MAP) kinase pathway, does not use sequestration to prevent misactivation of the mating response. Instead, Ste5 appears to use a conformation mechanism: Under basal conditions, intramolecular interaction of the PH domain with the VWA domain blocks the ability to coactivate the mating-specific MAPK, Fus3. Pheromone-induced membrane binding of Ste5 triggers release of this autoinhibition. Thus, in addition to serving as a conduit guiding kinase communication, Ste5 directly receives input information to decide if and when signal can be transmitted to mating output.