Positive Feedback Promotes Oscillations in Negative Feedback Loops
A simple three-component negative feedback loop is a recurring motif in biochemical oscillators. This motif oscillates as it has the three necessary ingredients for oscillations: a three-step delay, negative feedback, and nonlinearity in the loop. However, to oscillate, this motif under the common G...
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Public Library of Science
2014
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134231/ |
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pubmed-41342312014-08-19 Positive Feedback Promotes Oscillations in Negative Feedback Loops Ananthasubramaniam, Bharath Herzel, Hanspeter Research Article A simple three-component negative feedback loop is a recurring motif in biochemical oscillators. This motif oscillates as it has the three necessary ingredients for oscillations: a three-step delay, negative feedback, and nonlinearity in the loop. However, to oscillate, this motif under the common Goodwin formulation requires a high degree of cooperativity (a measure of nonlinearity) in the feedback that is biologically “unlikely.” Moreover, this recurring negative feedback motif is commonly observed augmented by positive feedback interactions. Here we show that these positive feedback interactions promote oscillation at lower degrees of cooperativity, and we can thus unify several common kinetic mechanisms that facilitate oscillations, such as self-activation and Michaelis-Menten degradation. The positive feedback loops are most beneficial when acting on the shortest lived component, where they function by balancing the lifetimes of the different components. The benefits of multiple positive feedback interactions are cumulative for a majority of situations considered, when benefits are measured by the reduction in the cooperativity required to oscillate. These positive feedback motifs also allow oscillations with longer periods than that determined by the lifetimes of the components alone. We can therefore conjecture that these positive feedback loops have evolved to facilitate oscillations at lower, kinetically achievable, degrees of cooperativity. Finally, we discuss the implications of our conclusions on the mammalian molecular clock, a system modeled extensively based on the three-component negative feedback loop. Public Library of Science 2014-08-15 /pmc/articles/PMC4134231/ /pubmed/25126951 http://dx.doi.org/10.1371/journal.pone.0104761 Text en © 2014 Ananthasubramaniam, Herzel http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Ananthasubramaniam, Bharath Herzel, Hanspeter |
| spellingShingle |
Ananthasubramaniam, Bharath Herzel, Hanspeter Positive Feedback Promotes Oscillations in Negative Feedback Loops |
| author_facet |
Ananthasubramaniam, Bharath Herzel, Hanspeter |
| author_sort |
Ananthasubramaniam, Bharath |
| title |
Positive Feedback Promotes Oscillations in Negative Feedback Loops |
| title_short |
Positive Feedback Promotes Oscillations in Negative Feedback Loops |
| title_full |
Positive Feedback Promotes Oscillations in Negative Feedback Loops |
| title_fullStr |
Positive Feedback Promotes Oscillations in Negative Feedback Loops |
| title_full_unstemmed |
Positive Feedback Promotes Oscillations in Negative Feedback Loops |
| title_sort |
positive feedback promotes oscillations in negative feedback loops |
| description |
A simple three-component negative feedback loop is a recurring motif in biochemical oscillators. This motif oscillates as it has the three necessary ingredients for oscillations: a three-step delay, negative feedback, and nonlinearity in the loop. However, to oscillate, this motif under the common Goodwin formulation requires a high degree of cooperativity (a measure of nonlinearity) in the feedback that is biologically “unlikely.” Moreover, this recurring negative feedback motif is commonly observed augmented by positive feedback interactions. Here we show that these positive feedback interactions promote oscillation at lower degrees of cooperativity, and we can thus unify several common kinetic mechanisms that facilitate oscillations, such as self-activation and Michaelis-Menten degradation. The positive feedback loops are most beneficial when acting on the shortest lived component, where they function by balancing the lifetimes of the different components. The benefits of multiple positive feedback interactions are cumulative for a majority of situations considered, when benefits are measured by the reduction in the cooperativity required to oscillate. These positive feedback motifs also allow oscillations with longer periods than that determined by the lifetimes of the components alone. We can therefore conjecture that these positive feedback loops have evolved to facilitate oscillations at lower, kinetically achievable, degrees of cooperativity. Finally, we discuss the implications of our conclusions on the mammalian molecular clock, a system modeled extensively based on the three-component negative feedback loop. |
| publisher |
Public Library of Science |
| publishDate |
2014 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134231/ |
| _version_ |
1613124764302311424 |