l17. robustness in bacterial chemotaxis response lingchong you bme 265-05. march 22, 2005

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