Conformational control of the Ste5 scaffold protein insulates against MAP kinase misactivation

Science. 2012 Sep 7;337(6099):1218-22. doi: 10.1126/science.1220683. Epub 2012 Aug 9.

Abstract

Cells reuse signaling proteins in multiple pathways, raising the potential for improper cross talk. 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 kinase (MAPK) pathway, does not use sequestration to prevent misactivation of the mating response. Instead, Ste5 appears to use a conformation mechanism: Under basal conditions, an intramolecular interaction of the pleckstrin homology (PH) domain with the von Willebrand type A (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.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Enzyme Activation
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Models, Biological
  • Phosphorylation
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Protein Kinases / metabolism
  • Protein Precursors / metabolism
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae / physiology
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • MF(ALPHA)1 protein, S cerevisiae
  • Protein Precursors
  • STE5 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Protein Kinases
  • FUS3 protein, S cerevisiae
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • Ste11 protein, S cerevisiae
  • Mitogen-Activated Protein Kinase Kinases
  • STE7 protein, S cerevisiae

Associated data

  • PDB/4F2H