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      Machines vs. Ensembles: Effective MAPK Signaling through Heterogeneous Sets of Protein Complexes

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      1 , 1 , 2 , *
      PLoS Computational Biology
      Public Library of Science

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          Abstract

          Despite the importance of intracellular signaling networks, there is currently no consensus regarding the fundamental nature of the protein complexes such networks employ. One prominent view involves stable signaling machines with well-defined quaternary structures. The combinatorial complexity of signaling networks has led to an opposing perspective, namely that signaling proceeds via heterogeneous pleiomorphic ensembles of transient complexes. Since many hypotheses regarding network function rely on how we conceptualize signaling complexes, resolving this issue is a central problem in systems biology. Unfortunately, direct experimental characterization of these complexes has proven technologically difficult, while combinatorial complexity has prevented traditional modeling methods from approaching this question. Here we employ rule-based modeling, a technique that overcomes these limitations, to construct a model of the yeast pheromone signaling network. We found that this model exhibits significant ensemble character while generating reliable responses that match experimental observations. To contrast the ensemble behavior, we constructed a model that employs hierarchical assembly pathways to produce scaffold-based signaling machines. We found that this machine model could not replicate the experimentally observed combinatorial inhibition that arises when the scaffold is overexpressed. This finding provides evidence against the hierarchical assembly of machines in the pheromone signaling network and suggests that machines and ensembles may serve distinct purposes in vivo. In some cases, e.g. core enzymatic activities like protein synthesis and degradation, machines assembled via hierarchical energy landscapes may provide functional stability for the cell. In other cases, such as signaling, ensembles may represent a form of weak linkage, facilitating variation and plasticity in network evolution. The capacity of ensembles to signal effectively will ultimately shape how we conceptualize the function, evolution and engineering of signaling networks.

          Author Summary

          Intracellular signaling networks are central to a cell's ability to adapt to its environment. Developing the capacity to effectively manipulate such networks would have a wide range of applications, from cancer therapy to synthetic biology. This requires a thorough understanding of the mechanisms of signal transduction, particularly the kinds of protein complexes that are formed during transmission of extracellular information to the nucleus. Traditionally, signaling complexes have been largely perceived (albeit often implicitly) as machine-like structures. However, the number of molecular complexes that could theoretically be formed by complex signaling networks is astronomically large. This has led to the pleiomorphic ensemble hypothesis, which posits that diverse and rapidly changing sets of transient protein complexes can transmit and process information. Our goal was to use computational approaches, specifically rule-based modeling, to test these hypotheses. We constructed a model of the prototypical yeast mating pathway and found significant ensemble-like behavior. Our results thus demonstrated that ensembles can in fact transmit extracellular signals with minimal noise. Additionally, a comparison of this model with one tailored to generate machine-like complexes displayed notable phenotypic differences, revealing potential advantages for ensemble-like signaling. Our demonstration that ensembles can function effectively will have a significant impact on how we conceptualize signaling and other processes inside cells.

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          High-density mapping of single-molecule trajectories with photoactivated localization microscopy.

          We combined photoactivated localization microscopy (PALM) with live-cell single-particle tracking to create a new method termed sptPALM. We created spatially resolved maps of single-molecule motions by imaging the membrane proteins Gag and VSVG, and obtained several orders of magnitude more trajectories per cell than traditional single-particle tracking enables. By probing distinct subsets of molecules, sptPALM can provide insight into the origins of spatial and temporal heterogeneities in membranes.
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            Breaking the diffraction barrier: super-resolution imaging of cells.

            Anyone who has used a light microscope has wished that its resolution could be a little better. Now, after centuries of gradual improvements, fluorescence microscopy has made a quantum leap in its resolving power due, in large part, to advancements over the past several years in a new area of research called super-resolution fluorescence microscopy. In this Primer, we explain the principles of various super-resolution approaches, such as STED, (S)SIM, and STORM/(F)PALM. Then, we describe recent applications of super-resolution microscopy in cells, which demonstrate how these approaches are beginning to provide new insights into cell biology, microbiology, and neurobiology. Copyright © 2010 Elsevier Inc. All rights reserved.
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              The cell as a collection of protein machines: preparing the next generation of molecular biologists.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Comput Biol
                PLoS Comput. Biol
                plos
                ploscomp
                PLoS Computational Biology
                Public Library of Science (San Francisco, USA )
                1553-734X
                1553-7358
                October 2013
                October 2013
                10 October 2013
                : 9
                : 10
                : e1003278
                Affiliations
                [1 ]Center for Bioinformatics, University of Kansas, Lawrence, Kansas, United States of America
                [2 ]Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, United States of America
                Fox Chase Cancer Center, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RS EJD. Performed the experiments: RS. Analyzed the data: RS EJD. Wrote the paper: RS EJD.

                Article
                PCOMPBIOL-D-13-00416
                10.1371/journal.pcbi.1003278
                3794900
                24130475
                863db717-f873-4f31-b3b3-b7f16e7789bd
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 8 March 2013
                : 30 August 2013
                Page count
                Pages: 11
                Funding
                This work was supported by startup funds from the University of Kansas. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article

                Quantitative & Systems biology
                Quantitative & Systems biology

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