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Published October 13, 2009 | Published + Supplemental Material
Journal Article Open

Quantitative effect of scaffold abundance on signal propagation

Abstract

Protein scaffolds bring together multiple components of a signalling pathway, thereby promoting signal propagation along a common physical 'backbone'. Scaffolds play a prominent role in natural signalling pathways and provide a promising platform for synthetic circuits. To better understand how scaffolding quantitatively affects signal transmission, we conducted an in vivo sensitivity analysis of the yeast mating pathway to a broad range of perturbations in the abundance of the scaffold Ste5. Our measurements show that signal throughput exhibits a biphasic dependence on scaffold concentration and that altering the amount of scaffold binding partners reshapes this biphasic dependence. Unexpectedly, the wild-type level of Ste5 is ~ 10-fold below the optimum needed to maximize signal throughput. This sub-optimal configuration may be a tradeoff as increasing Ste5 expression promotes baseline activation of the mating pathway. Furthermore, operating at a sub-optimal level of Ste5 may provide regulatory flexibility as tuning Ste5 expression up or down directly modulates the downstream phenotypic response. Our quantitative analysis reveals performance tradeoffs in scaffold-based modules and defines engineering challenges for implementing molecular scaffolds in synthetic pathways.

Additional Information

© 2009 EMBO and Macmillan Publishers Limited. Received 19 November 2008; Accepted 9 September 2009; Published online 13 October 2009. We thank the members of the Asthagiri and Deshaies laboratories for helpful discussions and guidance with experiments; D Chan, R Deshaies, C Smolke, E Elion and W Lim for reagents and E Davidson, R Deshaies and P Sternberg for comments on the manuscript. This work was supported by the Institute for Collaborative Biotechnologies through Grant DAAD19-03-D-0004 from the US Army Research Office. SAC was supported by the NIH Molecular Cell Biology Training Grant NIH/NRSA 5T32GM07616. This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits distribution and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.

Attached Files

Published - Chapman2009p6354Mol_Syst_Biol.pdf

Supplemental Material - msb200973-dfs2a.txt

Supplemental Material - msb200973-dfs4.txt

Supplemental Material - msb200973-dfs5.txt

Supplemental Material - msb200973-s1.pdf

Supplemental Material - msb200973-s2.xls

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