Sunday, July 18, 2010

Chemotaxis CheZ position experiments


Bacteria swim by their noses. That is, they smell food and swim towards it; they smell waste and swim away. The molecular basis of this amazing feat is the most well studied molecular signal transduction system and as such serves as a model for other lessor-studied bio-molecular signaling.

There's one little detail of the chemotaxis system that caught my attention a few years ago. The signal is transmitted from sensor to motors via a diffusing molecule called "CheY". When CheY has a phosphoryl group attached to it, it activates the motors in a certain way; when it loses that group it reverses the motors.

There's a very interesting subtlety to this system. The part of the system which "charges" the transmitter (to borrow electrical engineering terminology) is a kinase called CheA. The "discharging circuit" is the enzyme CheZ. It turns out that these two enzymes are, counter-intuitively, co-located. That is, it seems odd that the enzymes responsible for pulling-up a signal are co-located with the enzymes that pull it down. It would appear that the system is spinning it's wheels -- undoing what it just did. Why shouldn't it have the pull-down phosphatase evenly distributed or co-located with the motors?

When I first read this detail a few years ago in Eisenbach's book "Chemotaxis" it mentioned this counter-intuitive fact and I thought to myself, "I bet I know why -- it reduces saturation and evens out the signal." I wrote a little simulation years ago and convinced myself that this was indeed the case (at least for my toy simulation). Then I got distracted for years didn't get around to improving the simulations.

My hypothesis is that by co-locating CheZ and CheA the signal will saturate less near the transmitter and become more spatially uniform. My intuition is that when the external signal is rising and transmitter wishes to control the motors it needs a supply of free un-phosphorylated CheY in order to communicate this. Because CheY is produced at one end and diffuses to the other regions, there's a 1/r^2 distribution of it as it produces it. If it turns on the transmitter at some moment then a few moments later there will be an excess of CheY~P near the transmitter but a lot less further away. But, if CheZ is located nearby the transmitter then it is right where it is needed most -- where there's an excess of CheY~P.

Honestly, it's easier to see the effect than to describe it.

In the following figures, the top row has the CheZ co-located with CheA on the left side. The bottom row has the same amount of CheZ evenly distributed. These are space-time plots. Space is on the X axis with the transmitter on the left. Time progresses from the bottom of the graph towards the top. The right plot is the power spectrum of the right most spatial position which simulates the most distant motor's response. In the top row we see two things. First, the distribution is much smoother from left to right than it is in the bottom row. This is good for the bacteria as the motors are scattered throughout the cell and the controller depends on them to synchronously changing state as it switches from laminar movement to chaotic tumbling. Second, the non-linear clipping harmonic (the little spike on the right) is taller in the bottom row and the primary response (the big peak) is a little smaller. This indicates that there's a (mild) fidelity improvement in the co-location of CheA and CheZ. Given the simplicity of this argument I submit that such co-location is probably a common motif in other kinase/phosphatase (and similar pull-up/pull-down type) systems.

Caveats -- this is a scale-free simulation. I made no attempt to model actual parameters but rather went on the assumption that the bacteria probably operates near peak efficiency so I just twiddled the parameters until I saw what appeared to be peak efficiency. Of course, this is hardly rigorous so the next step will be to try to get accurate rate and diffusion constants. If anyone knows where they are conveniently located in one paper, that would be nice. :-)

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