Bacterial Chemotaxis

1. Bacterial Chemotaxis Dr. Chrisantha Fernando Systems Biology Centre University of Birmingham, UK March 2007

2. 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.

3. Rating 18: Neutrophil follows and kills bacteria

4. What is Chemotaxis? Rapid Response

6. Can’t measure spatial gradients! Difference in [chemical] too small to be detected

7. Runs and Tumbles Berg, Brown…, 1972

9. Due to Clockwise or Anti-Clockwise of Flagella Motor

10. Adaptation of tumbling frequency EXACT Well mixed reactor Measure tumbles Add attractant Adaptation time Add attractant

11. Exact Adaptation • The steady state tumbling frequency is independent of the attractant concentration.

12. 6 proteins control this computation. Adler. Mechanism? Attractant binds Receptor/Kinase 1000 receptors Kentner and Sourjik 30 binding sites for CheY on motor = Cooperativity. CheY-P increases the prob. that motor turns clockwise, I.e producing tumbling. Clockwise/Anti-Clock

14. Add attractant Attractant shuts off kinase CheY gets de-phosphorylated Tumbles decrease rapidly But how does adaptation occur, i.e increased tumbling again?

15. Adaptation Methylation can sensitize the detector This happens slowly, to an extent determined by two oppositely acting proteins.

16. CheR methylates and sensitizes CheB de-methylates and desensitizes CheB is activated by CheY-P, i.e. negative feedback loop.

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

19. 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”.

21. Robust feature Not robust Not robust

23. 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?

24. [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.

26. CheB + + Active Em = Output E CheR Input u Inactive Tar complex (E) in methylated and unmethylated form Ligand binds to methylated form only, and inactivates We require a steady fixed active Em. So, in proportion to [Em] active, we destroy Em This means, if [u] is increased, there is less Em, so less destruction of Em so, [Em] again increases to its steady state. Or, if [u] is decreased, [Em] is increased, and so Em destruction rate increases so again reducing [Em] to steady state. Em

27. Binds to only Methylated receptors Chemoattractant [Active receptor] Rate of de-methylation By CheB

29. Problems with Current Explanations • Explaining how the Tar complex can be so sensitive (high gain) over many orders of magnitude.

31. Dennis Bray : Outstanding Issues • http://www.pdn.cam.ac.uk/groups/comp-cell/Questions.html