bacterial chemotaxis dr. chrisantha fernando systems biology centre university of birmingham, uk...

Bacterial ChemotaxisBacterial Chemotaxis

Dr. Chrisantha Fernando

Systems Biology Centre

University of Birmingham, UK

March 2007

Dr. Chrisantha Fernando

Systems Biology Centre

University of Birmingham, UK

March 2007

Thanks to…Thanks to…

Uri Alon. The core of this lecture is based on a lecture given by Uri Alon, available at

http://www.weizmann.ac.il/mcb/UriAlon/

Actually you can even here him giving the lecture in audio. I highly recommend it.

Uri Alon. The core of this lecture is based on a lecture given by Uri Alon, available at


Actually you can even here him giving the lecture in audio. I highly recommend it.



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are needed to see this picture.

Rating 18: Neutrophil follows and kills bacteria

What is Chemotaxis? What is Chemotaxis?

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Rapid Response

Can’t measure spatial gradients!Can’t measure spatial gradients!

Difference in [chemical] too small to be detected

Runs and TumblesRuns and Tumbles



Berg, Brown…, 1972

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Due to Clockwise or Anti-Clockwise of Flagella MotorDue to Clockwise or Anti-

Clockwise of Flagella Motor



Adaptation of tumbling frequency

Adaptation of tumbling frequency



Well mixed reactor

Measure tumbles

Add attractant

Add attractant

EXACT

Adaptation time

Exact AdaptationExact Adaptation

The steady state tumbling frequency is independent of the attractant concentration.

The steady state tumbling frequency is independent of the attractant concentration.



Mechanism?Mechanism?



6 proteins control this computation. Adler.

Clockwise/Anti-Clock

Attractant binds

1000 receptorsReceptor/Kinase

CheY-P increases the prob. that motor turns clockwise, I.e producing tumbling.

30 binding sites for CheY on motor = Cooperativity.

Kentner and Sourjik

Add attractantAdd attractant



Attractant shuts off kinase

CheY gets de-phosphorylated

Tumbles decrease rapidly

But how does adaptation occur, i.e increased tumbling again?

AdaptationAdaptation



Methylation can sensitize the detector

This happens slowly, to an extent determined by two oppositely acting proteins.



CheR methylatesand sensitizes

CheB de-methylatesand desensitizes

CheB is activated byCheY-P, i.e. negative

feedback loop.

How robust is this circuit to change in protein concentration? Uri Alon asked whether it was “fine tuned” or “robust”.

How robust is this circuit to change in protein concentration? Uri Alon asked whether it was “fine tuned” or “robust”.





Behaviour Styles!

Experiments to alter protein levels in real bacteria.

Experiments to alter protein levels in real bacteria.

Compute average tumbling frequency of population using image processing.

A variety of individual differences were found even in genetically identical organisms: “nervous” vs. “relaxed”.

Compute average tumbling frequency of population using image processing.

A variety of individual differences were found even in genetically identical organisms: “nervous” vs. “relaxed”.



Robust feature

Not robust

Not robust

Why is exact adaptation robust? Why is exact adaptation robust?

Adaptation time and tumbling frequency is not robust.

Mutants with only partial adaptation (no CheR and CheB) have 1% normal chemotaxis ability.

Hypothesis: Chemotaxis mechanism evolved so that exact adaptation was robust to variation in protein level changes.

Is it possible to have a good chemotaxis mechanism without exact adaptation?

Adaptation time and tumbling frequency is not robust.

Mutants with only partial adaptation (no CheR and CheB) have 1% normal chemotaxis ability.

Hypothesis: Chemotaxis mechanism evolved so that exact adaptation was robust to variation in protein level changes.

Is it possible to have a good chemotaxis mechanism without exact adaptation?

[Protein] is noisy[Protein] is noisy

Sometimes only ~20 copies of a protein in a cell. This will vary due to noise in transcription and translation.

Imagine making a circuit that had to be robust to very unreliable and poorly specified electrical parts.

Sometimes only ~20 copies of a protein in a cell. This will vary due to noise in transcription and translation.

Imagine making a circuit that had to be robust to very unreliable and poorly specified electrical parts.





E Em

Em

= OutputActive

Inactive

Input u

+CheB+

CheR

1. Tar complex (E) in methylated and unmethylated form2. Ligand binds to methylated form only, and inactivates3. We require a steady fixed active Em. 4. So, in proportion to [Em] active, we destroy Em

5. This means, if [u] is increased, there is less Em, so less destruction of Em so, [Em] again increases to its steady state. 6. Or, if [u] is decreased, [Em] is increased, and so Em destruction rate increases so again reducing [Em] to steady state.



Chemoattractant [Active receptor]

Rate of de-methylation By CheB

Binds to only Methylated receptors



Problems with Current Explanations

Problems with Current Explanations

Explaining how the Tar complex can be so sensitive (high gain) over many orders of magnitude.

Explaining how the Tar complex can be so sensitive (high gain) over many orders of magnitude.



Dennis Bray : Outstanding IssuesDennis Bray : Outstanding Issues

http://www.pdn.cam.ac.uk/groups/comp-cell/Questions.html

http://www.pdn.cam.ac.uk/groups/comp-cell/Questions.html

bacterial chemotaxis dr. chrisantha fernando systems biology centre university of birmingham, uk...

Documents

robust slide

sourjik slide

exact adaptation robust

rapid response slide

partial adaptation

adaptation methylation

attractant attractant

uri alon