Conformational Control of the Ste5 Scaffold Protein Insulates Against MAP Kinase Misactivation

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA.
Science (Impact Factor: 33.61). 08/2012; 337(6099):1218-22. DOI: 10.1126/science.1220683
Source: PubMed


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.

Download full-text


Available from: Scott Coyle, Dec 16, 2013
  • Source
    • "Which module is activated by the switch depends on, e.g., an environmental factor. An example of a switch may be found in the MAPK pathway, where growth conditions determine which MAPK protein is produced (Zalatan et al. 2012). Downstream the proteins may activate different regulatory modules. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Many pathways are dysregulated in cancer. Dysregulation of the regulatory network results in less control of transcript levels in the cell. Hence, dysregulation is reflected in the heterogeneity of the transcriptome: the more dysregulated the pathway, the more the transcriptomic heterogeneity. We identify four scenarios for a transcriptomic heterogeneity increase (i.e., pathway dysregulation) in cancer: (1) activation of a molecular switch, (2) a structural change in a regulator, (3) a temporal change in a regulator, and (4) weakening of gene–gene interactions. These mechanisms are statistically motivated, explored in silico, and their plausibility to occur in vivo illustrated by means of oncogenomics data of breast cancer studies. Electronic supplementary material The online version of this article (doi:10.1007/s11538-015-0103-7) contains supplementary material, which is available to authorized users.
    Full-text · Article · Sep 2015 · Bulletin of Mathematical Biology
  • Source
    • "However, the mechanisms of scaffold assembly and its role in generating cellular responses remain unclear. A yeast scaffold protein, Ste5, involved in the mating MAP kinase pathway is known to function as a modular organizing center for the assembly of mating signaling proteins [7], [8]. Previous studies have revealed that individual docking interactions of Ste5 scaffold with its member kinases in the upper tier of the pathway -Ste11 (MAPKKK) and Ste7 (MAPKK)- could be functionally replaced by heterologous protein interactions and that such wiring was sufficient to restore pathway connectivity [9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Formation of signaling protein complexes is crucial for proper signal transduction. Scaffold proteins in MAP kinase pathways are thought to facilitate complex assembly, thereby promoting efficient and specific signaling. To elucidate the assembly mechanism of scaffold complexes in mammals, we attempted to rationally rewire JIP1-dependent JNK MAP kinase pathway via alternative assembly of JIP1 complex. When JIP1-JNK docking interaction in the complex was replaced with heterologous protein interaction domains, such as PDZ domains and JNK-binding domains, a functional scaffold complex was reconstituted, and JNK signaling was rescued. Reassembly of JIP1 complex using heterologous protein interactions was sufficient for restoring of JNK MAP kinase pathway to induce signaling responses, including JNK activation and cell death. These results suggest a simple yet modular mechanism for JIP1 scaffold assembly in mammals.
    Full-text · Article · May 2014 · PLoS ONE
  • Source
    • "In the cytosol, signals can transmit through the large assemblies, such as the nucleosomes in the nucleus; and as we argue here, also through the structured cytoskeleton, which is similarly dynamic. In all cases, scaffolding proteins [103] [105] [106] which are sometimes overlooked in cellular diagrams are likely to play major roles. Scaffolding proteins do not communicate the signal passively; they can control it [103]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The spatial structure of the cell is highly organized at all levels: from small complexes and assemblies, to local nano- and microclusters, to global, micrometer scales across and between cells. We suggest that this multiscale spatial cell organization also organizes signaling and coordinates cellular behavior. We propose a new view of the spatial structure of cell signaling systems. This new view describes cell signaling in terms of dynamic allosteric interactions within and among distinct, spatially organized transient clusters. The clusters vary over time and space and are on length scales from nanometers to micrometers. When considered across these length scales, primary factors in the spatial organization are cell membrane domains and the actin cytoskeleton, both also highly dynamic. A key challenge is to understand the interplay across these multiple scales, link it to the physicochemical basis of the conformational behavior of single molecules and ultimately relate it to cellular function. Overall, our premise is that at these scales, cell signaling should be thought of not primarily as a sequence of diffusion-controlled molecular collisions, but instead transient, allostery-driven cluster re-forming interactions.
    Preview · Article · Aug 2013 · Physical Biology
Show more