Abstract
Cyanobacteria are the simplest known cellular systems that regulate their biological activities in daily cycles. For the cyanobacterium Synechococcus elongatus, it has been shown by in vitro and in vivo experiments that the basic circadian timing process is based on rhythmic phosphorylation of KaiC hexamers. Despite the excellent experimental work, a full systems level understanding of the in vitro clock is still lacking. In this work, we provide a mathematical approach to scan different hypothetical mechanisms for the primary circadian oscillator, starting from experimentally established molecular properties of the clock proteins. Although optimised for highest performance, only one of the in silico-generated reaction networks was able to reproduce the experimentally found high amplitude and robustness against perturbations. In this reaction network, a negative feedback synchronises the phosphorylation level of the individual hexamers and has indeed been realised in S. elongatus by KaiA sequestration as confirmed by experiments.
Highlights
The coordination of biological activities into daily cycles provides an important advantage for the fitness of diverse organisms, from bacteria to humans (Ouyang et al, 1998; Johnson and Golden, 1999; Sharma, 2003; Johnson, 2004; Woelfle et al, 2004)
Central to this coordination is an internal clock that drives gene expression in an approximate 24 h rhythm—a circadian clock found in most eukaryotes and, among prokaryotes, exclusively in cyanobacteria
We find that the most robust oscillatory network structure uses a negative feedback that has been realised in cyanobacteria by KaiA sequestration to low-phosphorylated KaiBC complexes
Summary
The coordination of biological activities into daily cycles provides an important advantage for the fitness of diverse organisms, from bacteria to humans (Ouyang et al, 1998; Johnson and Golden, 1999; Sharma, 2003; Johnson, 2004; Woelfle et al, 2004). Central to this coordination is an internal clock that drives gene expression in an approximate 24 h rhythm—a circadian clock found in most eukaryotes and, among prokaryotes, exclusively in cyanobacteria. Detailed functional and structural studies on Kai proteins revealed the following main properties: (i) KaiC monomers bind ATP to form a stable hexamer (Nishiwaki et al, 2000; Mori et al, 2002; Hayashi et al, 2003, 2006); (ii) KaiC has both autophosphorylation and dephosphorylation activities; in the absence of KaiA, about 20% of KaiC is phosphorylated (Nishiwaki et al, 2000; Tomita et al, 2005); (iii) a KaiC
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