l17. robustness in bacterial chemotaxis response lingchong you bme 265-05. march 22, 2005
TRANSCRIPT
L17. Robustness in bacterial chemotaxis response
Lingchong You
BME 265-05. March 22, 2005
• 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
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
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
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)
Brief review: network architecture system property
Negative feedback(no time delay)
Negative feedback(+ long time delay)
Positive feedback
-
-
+
Homeostasis
Switch, bistability
Oscillations
Oscillator based on negative feedback only
Oscillator based on activator-inhibitor architecture
Robustness by communication
• Coordination • Large numbers
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
Typical simulation results
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)
Long term monitoring of circuit dynamics
Balaggade, You et al. 2005, submitted
Robustness in bacterial chemotaxis
Fluorescent flagellar filaments of E. coli.
Random walk by E. coli
Berg, Physics Today, “Motile behavior of bacteria” (http://www.aip.org/pt/jan00/berg.htm)
Tumble
Run
Clockwise Counter-clockwise
Attractant(e.g. nutrient)
Repellent(e.g. toxin)
Chemotaxis: reduction in tumbling frequency to drive swimming toward attractant
Input
regulation
Output
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
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)
McAdams, et al 2004. Nat. Rev. Genetics
Alon et al 1999. Nature
R: CheRW: CheWA: CheAB: CheBY: CheYY-p: phosphorylated CheY
More simplified view
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)
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
Barkai & Leibler 1997, Nature
Perfect adaptation: Always returns to the same steady state
Adaptation precision robust to perturbations
stimulated
unstimulated
AP
A
Adaptation time NOT robust
Experiment: perfect adaptation
No stimulation
Stimulated by attractant(1mM L-aspartate)
Experimental measurements
Perfect adaptation(Robust)
Highly variable adaptation time & s.s. tumbling frequency
Not robust
Stimulted freq
unstimulted freqP
Changes in other parameters
Also: • perfect adaptation precision• highly variant steady state levels and adaptation time
Not robust Robust
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
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.
A highly simplified view of chemotaxis response
Tyson et al. Current Opinion in Cell Biology 2003, 15:221–231
Input
Output