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Peter's MOAC PhD

I undertook my Bioinformatics PhD at the MOAC Doctoral Training Centre (2004 to 2008), and graduated at the July 2009 ceremony.

My supervisors were Dr. David Whitworth (Microbiology), and Dr. Bärbel Finkenstädt (Statistics), with Prof. David Hodgson (Microbiology) and Prof. David Rand (Mathematics / Systems Biology) as advisors.

My independent advisory committee were Hugo van den Berg (Mathematics / Systems Biology), Andrew Mead (Warwick HRI) and David Scanlan (Biology).

The Topic - Two Component Systems

I am interested in Two Component Systems (TCS), a signalling mechanism used in most bacteria (and even some eukaryotes such as yeast and plants) explained below.

Two Component Systems (TCS)
[Diagram of simple Two Component System (TCS)]
In a typical TCS there are two proteins, the Sensor Kinase (or Histidine Kinase) which is the signal sensor, and a Response Regulator which does something as a result of this signal.
  1. The Input domain of the Sensor Kinase receives some signal.
  2. This causes autophosphorytlation of the Transmitter Domain at a specific histidine residue (H).
  3. The Sensor Kinase and Response Regulator dock, bringing the Transmitter Domain and Receiver Domain into close proximity.
  4. The phosphoryl group is transferred from the histidine residue (H) of the Transmitter Domain to a specific aspartate residue (D) on the Reciever Domain.
  5. When the Receiver Domain is phosphorylated this activates the Output Domain, causing some response to the original signal.

In a typical TCS, the transmitter and receiver are in two separate proteins found next to each other in the genome. We refer to genes containing two domains as hybrid proteins, while genes isolated from their apparent partner are called orphans.

The Bacteria - Myxococcus xanthus

My biology supervisors' favourite bacteria, Myxococcus xanthus (or myxo for short), is a social predatory soil dwelling bacteria with an unusually high number of TCSs, which we believe control its complex life cycle. A high proportion of these are orphaned - which means it is not clear what their partners are. As a result, a large part of the "wiring" for the myxo signalling network is unknown.

Unfortunately M. xanthus is not quite as easy to manipulate as the microbiologist's favourite bacteria, E. coli. Instead we have been testing putative transmitter/receiver interactions in yeast, using a technique called the Yeast Two Hybrid Assay, which I used during my first MOAC mini-project, summarised in this A1 Poster flowchart[PowerPoint] (~1.25 MB) (or as an image [PNG Image]). The group has also started working with a bacterial version of the same assay.

The Research - Predicting TCS interactions

During my PhD I used a range of mathematical, statistical and bioinformatics tools (see also my Python pages, and my R pages) to look at these TCS interactions and how they achieve specificity, with a view to predicting transmitter receiver pairs from their amino acid sequences. Hopefully we will also be able to test these results experimentally. This should allow us to determine the signalling network in M. xanthus, which could then be further modelled.

See also my list of publications.

Further Reading

I suggest these reviews for anyone interested in finding out more about this area:

[Cover of Current Opinion in Microbiology] Two-component and phosphorelay signal transduction

J.A. Hoch
Current Opinion in Microbiology, 2000, 3(2), 165–170.

[Cover of Current Microbiology and Molecular Biology Reviews] Social and developmental biology of the myxobacteria

L.J. Shimkets
Microbiology and Molecular Biology Reviews, 1990, 54(4), 473-501.

[Cover of Myxobacteria: Multicellularity and Differentiation] Myxobacteria: Multicellularity and Differentiation

Editor: David E. Whitworth
ASM Press 2007
ISBN: 978-1-55581-420-5


[PHOTO]

My supervisors:

[PHOTO]
Dr. David Whitworth
(Microbiology)

[PHOTO]
Dr. Bärbel Finkenstädt
(Statistics)

Advisors:

[PHOTO]
Prof. David Hodgson
(Microbiology)

[PHOTO]
Prof. David Rand
(Mathematics /
Systems Biology)

 

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