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

View/ Open
Issue Date
2013-10-10Author
Suderman, Ryan
Deeds, Eric J.
Publisher
Public Library of Science
Type
Article
Article Version
Scholarly/refereed, publisher version
Rights
Copyright: ©2013 Suderman, Deeds. 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.
Metadata
Show full item recordAbstract
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.
Description
A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author’s publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.
Collections
Citation
Suderman R, Deeds EJ (2013) Machines vs. Ensembles: Effective MAPK Signaling through Heterogeneous Sets of Protein Complexes. PLoS Comput Biol 9(10): e1003278. http://dx.doi.org/10.1371/journal.pcbi.1003278
Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.
We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.
Except where otherwise noted, this item's license is described as: Copyright: ©2013 Suderman, Deeds. 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.