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Quantifying Tissue-Specific Proteostatic Decline in Caenorhabditis elegans
Published on: September 7, 2021
Protein sequestration generates a flexible ultrasensitive response in a genetic network
Nicolas E Buchler1, Frederick R Cross
1The Rockefeller University, New York, NY 10065, USA. buchler@rockefeller.edu
Molecular Systems Biology
|May 21, 2009
Summary
Protein sequestration converts graded cellular responses into ultrasensitive ones. This tunable mechanism, observed in yeast, offers an adaptive advantage and explains the evolution of dominant negatives.
Area of Science:
- Molecular Biology
- Systems Biology
- Genetics
Background:
- Cellular regulation relies on ultrasensitive responses.
- Protein sequestration is a potential mechanism for generating ultrasensitivity.
- Dominant-negative proteins can inhibit active proteins.
Purpose of the Study:
- To investigate if protein sequestration can generate ultrasensitivity in a synthetic genetic circuit.
- To model and experimentally validate the relationship between inhibitor abundance and ultrasensitivity.
- To explore the evolutionary implications of dominant negatives.
Main Methods:
- Construction of a synthetic genetic circuit in budding yeast.
- Utilizing a dominant-negative inhibitor to sequester a transcription factor.
- Quantitative modeling of the genetic network.
- Experimental validation of model predictions through mutation and observation.
Main Results:
- Sequestration of a transcription factor by a dominant-negative inhibitor induced ultrasensitivity.
- Observed apparent Hill coefficients up to 12, indicating sharply ultrasensitive responses.
- Demonstrated that inhibitor abundance tunes both the threshold and degree of ultrasensitivity.
- Experimental results aligned with quantitative model predictions.
Conclusions:
- Protein sequestration is a viable mechanism for generating tunable ultrasensitive cellular responses.
- The abundance of the inhibitor is a key factor in controlling ultrasensitivity.
- This mechanism provides a potential explanation for the evolutionary emergence of dominant-negative proteins.
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