title: Conformational control of the Ste5 scaffold protein insulates against MAP kinase misactivation.
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.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA.
authors.forename: Jesse G
authors.initials: JG
authors.lastname: Zalatan
authors.forename: Scott M
authors.initials: SM
authors.lastname: Coyle
authors.forename: Saravanan
authors.initials: S
authors.lastname: Rajan
authors.forename: Sachdev S
authors.initials: SS
authors.lastname: Sidhu
authors.forename: Wendell A
authors.initials: WA
authors.lastname: Lim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D004789:Enzyme Activation; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011494:Protein Kinases / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism* / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C048632:MF(ALPHA)1 protein, S cerevisiae; D011498:Protein Precursors; C080321:STE5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; C075580:FUS3 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C067018:Ste11 protein, S cerevisiae; D020929:Mitogen-Activated Protein Kinase Kinases; C119844:STE7 protein, S cerevisiae