L17. Robustness in bacterial chemotaxis response

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L17. Robustness in bacterial chemotaxis response
BME 265-05. March 22, 2005

• Lingchong You

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• Homework 12 graded pick in office during office
  hours
• No class March 24th. Instead, attend one or both
  of the following
• March 23, 300pm, 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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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 QA)

• 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
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Negative feedback (no time delay)
Homeostasis

Positive feedback
Switch, bistability
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Negative feedback ( long time delay)
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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Prototype a population control circuit
extinction
No cell-cell variations
AHL
?
I
R
R
survival
luxI
luxR
ccdB
With cell-cell variations
PluxI
CcdB
You et al, Nature (2004)
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Typical simulation results
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OFF
Typical dynamics in Top10F (pH7 34C)
ON

• Population behavior
• Stable regulation
• Damped oscillations
• Captured by model
• Mutants arose after 100 hrs

ON
OFF
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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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Clockwise
Counter-clockwise
Run
Tumble
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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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Perfect Adaptation in Bacterial Chemotaxis
Signaling
Segall, J. E., Block, S. M. Berg, H. E.
Temporal comparisons in bacterial
chemotaxis. Proc. Natl. Acad. Sci. USA 83,
8987-8991 (1986).
Adaptation precision
Yss
Y0
Asp
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Whats 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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More simplified view
R CheR W CheW A CheA B CheB Y CheY Y-p
phosphorylated CheY
Alon et al 1999. Nature
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A two-state model

• 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)
Barkai Leibler 1997 Nature
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Key assumptions

• Input ligand. Ligand binding and unbinding
  happens at the fastest time scale. Binding
  affinity is independent of receptors 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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Perfect adaptation Always returns to the same
steady state
Barkai Leibler 1997, Nature
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Adaptation precision robust to perturbations
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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
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Changes in other parameters
Not robust
Robust

• Also
• perfect adaptation precision
• highly variant steady state levels and
  adaptation time

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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
Input
Output
Tyson et al. Current Opinion in Cell Biology
2003, 15221231
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