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dc.contributor.authorKothamachu, Varun Bhaskar
dc.date.accessioned2017-03-15T18:30:40Z
dc.date.issued2016-08-19
dc.description.abstractIn 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.en_GB
dc.description.sponsorshipDorothy Hodgkin Studentship funded by EPSRC and Microsoft Research.en_GB
dc.identifier.citationKothamachu, 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.en_GB
dc.identifier.citationAmin, 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.en_GB
dc.identifier.citationKothamachu, 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.en_GB
dc.identifier.grantnumberMRL contract no. 2010-016en_GB
dc.identifier.urihttp://hdl.handle.net/10871/26597
dc.language.isoenen_GB
dc.publisherUniversity of Exeteren_GB
dc.relation.sourceChapter 4 used data from http://www.p2cs.orgen_GB
dc.rights.embargoreasonTo pursue publication of the research elsewhereen_GB
dc.subjectmultistabilityen_GB
dc.subjectprokaryotesen_GB
dc.subjecttwo component signalling networksen_GB
dc.subjectmultidomain proteinsen_GB
dc.subjectBoolean logicen_GB
dc.subjectsynthetic biologyen_GB
dc.subjectPhosphorylationen_GB
dc.subjectTopologyen_GB
dc.subjectSignal processingen_GB
dc.subjectCell signaling structuresen_GB
dc.subjectBacillus subtilisen_GB
dc.subjectBiochemical simulationsen_GB
dc.subjectChemotaxisen_GB
dc.subjectProtein kinaseen_GB
dc.subjectsignaling cascadeen_GB
dc.subjectSignal terminationen_GB
dc.subjectDynamic responseen_GB
dc.subjectmodellingen_GB
dc.subjectordinary differential equationsen_GB
dc.subjectODEen_GB
dc.subjectsteady stateen_GB
dc.subjectbistabilityen_GB
dc.titleAn investigation into dynamic and functional properties of prokaryotic signalling networksen_GB
dc.typeThesis or dissertationen_GB
dc.contributor.advisorAkman, Ozgur
dc.contributor.advisorSoyer, Orkun
dc.publisher.departmentMathematicsen_GB
dc.type.degreetitlePhD in Mathematicsen_GB
dc.type.qualificationlevelDoctoralen_GB
dc.type.qualificationnamePhDen_GB


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