Rewiring cell signaling: The logic and plasticity of eukaryotic protein circuitry

Department of Cellular and Molecular Pharmacology, California Institute for Quantitative Biomedical Research, University of California San Francisco, 600 16(th) Street, San Francisco, California 94143-2240, USA.
Current Opinion in Structural Biology (Impact Factor: 7.2). 01/2005; 14(6):690-9. DOI: 10.1016/
Source: PubMed


Living cells rival computers in their ability to process external information and make complex behavioral decisions. Many of these decisions are made by networks of interacting signaling proteins. Ongoing structural, biochemical and cell-based studies have begun to reveal several common principles by which protein components are used to specifically transmit and process information. Recent engineering studies demonstrate that these relatively simple principles can be used to rewire signaling behavior in a process that mimics the evolution of new phenotypic responses.

Download full-text


Available from: John Eugene Dueber, Aug 14, 2015
7 Reads
  • Source
    • "The computational framework suggested here can be useful for a quantitative analysis of these constraints and for the design of novel biomolecules with desired functions. The design of novel or rewired signaling and metabolic networks [78], for instance, inevitably invokes complex tradeoffs between different molecules and their properties, and these can also be encoded within the framework presented here. Recent advances in the application of deep sequencing to libraries of natural protein variants [79] [80] and of in vitro mutational repertoires selected for complex combinations of physical features, including stability , binding, and specificity profiles [34,36,81–83] are generating datasets comprising thousands of mutants that relate sequence changes to function at unprecedented resolution and coverage [84]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To carry out their activities biological macromolecules balance different physical traits, such as stability, interaction affinity, and selectivity. How such often-opposing traits are encoded in a macromolecular system is critical to our understanding of evolutionary processes and ability to design new molecules with desired functions. We present a framework for constraining design simulations to balance different physical characteristics. Each trait is represented by the equilibrium fractional occupancy of the desired state relative to its alternatives, ranging from none to full occupancy, and the different traits are combined using Boolean operators to effect a ‘fuzzy’-logic language for encoding any combination of traits. In another paper, we presented a new combinatorial-backbone design algorithm AbDesign where the fuzzy-logic framework was used to optimize protein backbones and sequences for both stability and binding affinity in antibody-design simulation. We now extend this framework and find that fuzzy-logic design simulations reproduce sequence and structure design principles seen in nature to underlie exquisite specificity on the one hand, and multispecificity on the other. The fuzzy-logic language is broadly applicable and could help define the space of tolerated and beneficial mutations in natural biomolecular systems and design artificial molecules that encode complex characteristics.
    Journal of Molecular Biology 10/2014; 426(24). DOI:10.1016/j.jmb.2014.10.002 · 4.33 Impact Factor
  • Source
    • "Recently, scaffolds in mammalian MAP kinase signaling pathways have been implicated as potential drug targets due to the critical role of scaffold-dependent assembly in signaling [3], [16]. Several studies suggested that docking interactions in yeast scaffold complexes are highly modular [17]–[19]. Nonetheless, assembly mechanisms of mammalian scaffolds are yet to be fully understood. "
    [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.
    PLoS ONE 05/2014; 9(5):e96797. DOI:10.1371/journal.pone.0096797 · 3.23 Impact Factor
  • Source
    • "kinases/phosphatases, ubiquitin ligases/de-ubiquitinases and nucleotide exchange factors ), which when activated by inputs, use their catalytic activity to output signal to downstream substrates. In addition to their catalytic subunits, node proteins often contain discrete protein–protein interaction domains or motifs that mediate associations with other members of the pathway and/or regulate their signaling behavior [2] [3]. Thus, these accessory domains can act as gating elements for node proteins much in the same way components like transistors help control current flow (output) in response to an applied voltage (input) in electronic circuitry. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tank-binding kinase 1 (TBK1) serves as an important component of multiple signaling pathways. While the majority of research on TBK1 has focused on its role in innate immunity, critical functions for TBK1 in autophagy and cancer are beginning to emerge. This review highlights recent structural and biochemical studies that provide insights into the molecular mechanism of TBK1 activation and summarizes what is known to date about TBK1 substrate selection. Growing evidence suggests that both processes rely on TBK1 subcellular localization, with a variety of adaptor proteins each directing TBK1 to discrete signaling complexes for different cellular responses. Further study of TBK1-mediated pathways will require careful consideration of TBK1 mechanisms of activation and specificity for proper dissection of these distinct signaling cascades.
    FEBS letters 02/2013; 587(8). DOI:10.1016/j.febslet.2013.01.059 · 3.17 Impact Factor
Show more