An investigation into dynamic and functional properties of prokaryotic signalling networks
Kothamachu, Varun Bhaskar
Thesis or dissertation
University of Exeter
Reason for embargo
To pursue publication of the research elsewhere
In this thesis, I investigate dynamic and computational properties of prokaryotic signalling architectures commonly known as the Two Component Signalling networks and phosphorelays. The aim of this study is to understand the information processing capabilities of different prokaryotic signalling architectures by examining the dynamics they exhibit. I present original investigations into the dynamics of different phosphorelay architectures and identify network architectures that include a commonly found four step phosphorelay architecture with a capacity for tuning its steady state output to implement different signal-response behaviours viz. sigmoidal and hyperbolic response. Biologically, this tuning can be implemented through physiological processes like regulating total protein concentrations (e.g. via transcriptional regulation or feedback), altering reaction rate constants through binding of auxiliary proteins on relay components, or by regulating bi-functional activity in relays which are mediated by bifunctional histidine kinases. This study explores the importance of different biochemical arrangements of signalling networks and their corresponding response dynamics. Following investigations into the significance of various biochemical reactions and topological variants of a four step relay architecture, I explore the effects of having different types of proteins in signalling networks. I show how multi-domain proteins in a phosphorelay architecture with multiple phosphotransfer steps occurring on the same protein can exhibit multistability through a combination of double negative and positive feedback loops. I derive a minimal multistable (core) architecture and show how component sharing amongst networks containing this multistable core can implement computational logic (like AND, OR and ADDER functions) that allows cells to integrate multiple inputs and compute an appropriate response. I examine the genomic distribution of single and multi domain kinases and annotate their partner response regulator proteins across prokaryotic genomes to find the biological significance of dynamics that these networks embed and the processes they regulate in a cell. I extract data from a prokaryotic two component protein database and take a sequence based functional annotation approach to identify the process, function and localisation of different response regulators as signalling partners in these networks. In summary, work presented in this thesis explores the dynamic and computational properties of different prokaryotic signalling networks and uses them to draw an insight into the biological significance of multidomain sensor kinases in living cells. The thesis concludes with a discussion on how this understanding of the dynamic and computational properties of prokaryotic signalling networks can be used to design synthetic circuits involving different proteins comprising two component and phosphorelay architectures.
Dorothy Hodgkin Studentship funded by EPSRC and Microsoft Research.
Kothamachu, V.B., Feliu, E., Wiuf, C., Cardelli, L., and Soyer, O.S. (2013). Phosphorelays Provide Tunable Signal Processing Capabilities for the Cell. PLoS Comput Biol 9, e1003322.
Amin, M., Kothamachu, V.B., Feliu, E., Scharf, B.E., Porter, S.L., and Soyer, O.S. (2014). Phosphate Sink Containing Two-Component Signaling Systems as Tunable Threshold Devices. PLoS Comput Biol 10, e1003890.
Kothamachu, V.B., Feliu, E., Cardelli, L., and Soyer, O.S. (2015). Unlimited multistability and Boolean logic in microbial signalling. Journal of The Royal Society Interface 12, 20150234.
PhD in Mathematics
MRL contract no. 2010-016
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