Download - L17. Robustness in bacterial chemotaxis response Lingchong You BME 265-05. March 22, 2005
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L17. Robustness in bacterial chemotaxis response
Lingchong You
BME 265-05. March 22, 2005
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• Homework 1&2 graded; pick in office during office hours
• No class March 24th. Instead, attend one or both of the following:– March 23, 3:00pm, 130 North Bldg, Richard
Watanabe: “Integrating Compartmental Models and Genetics to Understand Glucose Tolerance”
– March 24, 10am, CIEMAS auditorium B, Pak Kin Wong: “One In a Million” Bio-Nano- and Information Technologies for Controlling Complex Biological Systems
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presentation order Name email: @duke.edu Project topics
2 Blais, Pierre Emmanuel peb5 Stochastic simulation of bistability
5 Chaudhry, Rajeev rc16 circadian rhythms (with Ramlingam)
6 Chu, Edward William ewc4 circadian rhythms (with peter)?
3 Donahoe, Casey D cdd4 circadian rhythms (with Prangkio)
4 Hanson, Megan mmh13 viral infection
8 Koreishi, Anjum Faruk afk cell cycle
7 Lee, Jiwon jl54 cell-cell communication
1 Leung, Alan Tsun Lim atl6 circadian rhythms
10 Novick, Paul Andrew pan3 viral infection
3 Prangkio, Panchika pp9 circadian rhythms (with Donahoe)
5 Ramalingam, Sundhar sr20 circadian rhythms (with Chaudhry)
9 Polikov, Vadim vsp cytokines
Groups & topics
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Project assistance
• Week of 4/4-4/9; Each group must make ½ hr appointment with me to discuss your project progress.
• Week of 4/12-4/15; No class. Optional appointments with me to assist with your projects
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Tentative final presentation schedule (25 min/group, including Q&A)
Dates may change; you need to attend all presentations:
• 4/19: groups 1, 2, 3• 4/21: 4, 5, 6• 4/26: 7, 8, 9, 10
• Project report due by 5/1 (both electronic & paper copies)
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Brief review: network architecture system property
Negative feedback(no time delay)
Negative feedback(+ long time delay)
Positive feedback
-
-
+
Homeostasis
Switch, bistability
Oscillations
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Oscillator based on negative feedback only
Oscillator based on activator-inhibitor architecture
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Robustness by communication
• Coordination • Large numbers
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R
Prototype: a population control circuit
luxIccdB luxR
R
PluxI
I
CcdB
AHL
You et al, Nature (2004)
?
extinction
survival
No cell-cellvariations
With cell-cellvariations
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Typical simulation results
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1. Population behavior
2. Stable regulation
3. Damped oscillations
4. Captured by model
5. Mutants arose after ~100 hrs
OFF
ON
OFF
ON
Typical dynamics in Top10F’ (pH=7; 34C)
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Long term monitoring of circuit dynamics
Balaggade, You et al. 2005, submitted
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Robustness in bacterial chemotaxis
Fluorescent flagellar filaments of E. coli.
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Random walk by E. coli
Berg, Physics Today, “Motile behavior of bacteria” (http://www.aip.org/pt/jan00/berg.htm)
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Tumble
Run
Clockwise Counter-clockwise
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Attractant(e.g. nutrient)
Repellent(e.g. toxin)
Chemotaxis: reduction in tumbling frequency to drive swimming toward attractant
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Input
regulation
Output
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Y0 Yss
+ Asp
Adaptation precision =
Perfect Adaptation in Bacterial Chemotaxis SignalingSegall, J. E., Block, S. M. & Berg, H. E. Temporal comparisons in bacterial chemotaxis.Proc. Natl. Acad. Sci. USA 83, 8987-8991 (1986).
10
Y
YSS
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What’s the basis for perfect adaptation? Two explanations:
• The kinetic parameters are fine-tuned.– E. g.: Spiro et al. A model of excitation and
adaptation in bacterial chemotaxis. PNAS, 1997
• Perfect adaptation is a robust property of the underlying network.– Barkai & Leibler 1997, Nature (Modeling)– Alon et al 1999, Nature (Experiment)
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McAdams, et al 2004. Nat. Rev. Genetics
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Alon et al 1999. Nature
R: CheRW: CheWA: CheAB: CheBY: CheYY-p: phosphorylated CheY
More simplified view
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A two-state model
Barkai & Leibler 1997 Nature
Key reactions: • Binding and unbinding of the receptor complex to ligand• Methylation and demethylation of the complex• Each receptor complex may have several methylation sites• Phosphorylation and dephosphorylation of B
System activity (output): number of receptors in active form (different methylation states and occupancy of ligands affect the activity of each receptor state)
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Key assumptions
• Input = ligand. Ligand binding and unbinding happens at the fastest time scale. Binding affinity is independent of receptor’s activity and its degree of methylation.
• CheB only demethylates phosphorylated receptors.
• CheR works at saturating level, or methylation of receptors follows a constant rate.
• Demethylation is independent of ligand binding
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Barkai & Leibler 1997, Nature
Perfect adaptation: Always returns to the same steady state
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Adaptation precision robust to perturbations
stimulated
unstimulated
AP
A
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Adaptation time NOT robust
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Experiment: perfect adaptation
No stimulation
Stimulated by attractant(1mM L-aspartate)
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Experimental measurements
Perfect adaptation(Robust)
Highly variable adaptation time & s.s. tumbling frequency
Not robust
Stimulted freq
unstimulted freqP
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Changes in other parameters
Also: • perfect adaptation precision• highly variant steady state levels and adaptation time
Not robust Robust
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Summary
• The adaptation precision of the E. coli chemotaxis network is highly robust to perturbations
• Other system properties (steady state level or the adaptation time) are not robust.
• In general, for many biological systems, only some system properties are robust to perturbations, but others are often sensitive
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Why perfect adaptation
• Possible reason:– Compensation for continued stimulation– “Preparation” for responding to further stimuli– Evidence:
• Cells deficient in adaptation are poor in chemotaxis even if their steady state tumbling is similar to wild type
• Cells capable of perfect adaptation are similar to WT in chemotaxis even if their steady state tumbling is quite different.
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A highly simplified view of chemotaxis response
Tyson et al. Current Opinion in Cell Biology 2003, 15:221–231
Input
Output
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