Abstract
Many signaling proteins are built from simple, modular components, yet display highly complex signal-processing behavior. Here we explore how modular domains can be used to build an ultrasensitive switch—a nonlinear input/output function that is central to many complex biological behaviors. By systematically altering the number and affinity of modular autoinhibitory interactions, we show that we can predictably convert a simple linear signaling protein into an ultrasensitive switch.
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References
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Acknowledgements
We thank J. Christopher Anderson, Adam Arkin, Noah Helman, Anton Vila-Sanjurjo, Brian Yeh and Brad Zamft for comments and discussion of this manuscript as well as members of the Lim laboratory for scientific advice. This work was supported by the National Institutes of Health and the National Science Foundation Synthetic Biology Engineering Research Center (SynBERC).
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Contributions
J.E.D. designed and conducted experiments depicted in this paper as well as constructing/purifying many of the synthetic switches described; prepared manuscript with W.A.L. E.A.M. constructed/purified many of the switches described, conducted experiments, and created model for switch parameter prediction; edited manuscript. W.A.L. made a major contribution to the conception of the general design of ultrasensitive switches and played a general mentorship role; prepared manuscript with J.E.D.
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Supplementary information
Supplementary Fig. 1
Metric for relative activity of N-WASP switches based on half-time of actin polymerization. (PDF 553 kb)
Supplementary Fig. 2
Composition of switch linkers. (PDF 60 kb)
Supplementary Fig. 3
Intramolecular affinities must be properly tuned to generate a switch with targeted behavior: basal repression and sensitivity to external input. (PDF 40 kb)
Supplementary Fig. 4
Mutation of two peptide ligands in the five interaction switch (A.5.3b) reduces the Hill coefficient from ∼4 to 2.5. (PDF 37 kb)
Supplementary Fig. 5
Design and behavior of an AND-gate for three independent inputs. (PDF 139 kb)
Supplementary Table 1
Components used in switch construction and their properties (PDF 92 kb)
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Dueber, J., Mirsky, E. & Lim, W. Engineering synthetic signaling proteins with ultrasensitive input/output control. Nat Biotechnol 25, 660–662 (2007). https://doi.org/10.1038/nbt1308
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DOI: https://doi.org/10.1038/nbt1308
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