Circadian KaiC Phosphorylation: A Multi-Layer Network

Cong-Xin, Li; Chen, Xiaofang; Wang, Peng‐Ye; Wang, Wei-Chi

doi:10.1371/journal.pcbi.1000568

Cited by 9 publications

(6 citation statements)

References 48 publications

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“…Since the publication of the in vitro KaiABC rhythm (68), there have been many attempts to model this oscillator (9, 14, 23, 37, 45, 47, 48, 54, 58, 63, 66, 82, 85, 91, 99, 102, 110, 113) and probably others of which we are unaware. As a representative example, we proposed in 2007 a model that stochastically simulates the kinetics of KaiC hexamers and the degree of phosphorylation of each monomer in every hexamer ( Figure 3 a ) (63).…”

Section: Modeling the In Vitro Oscillatormentioning

confidence: 99%

The Cyanobacterial Circadian System: From Biophysics to Bioevolution

Johnson

Stewart

Egli

2011

Annu. Rev. Biophys.

116

118

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Recent studies have unveiled the molecular machinery responsible for the biological clock in cyanobacteria and found that it exerts pervasive control over cellular processes including global gene expression. Indeed, the entire chromosome undergoes daily cycles of topology/compaction! The circadian system comprises both a posttranslational oscillator (PTO) and a transcriptional/translational feedback loop (TTFL). The PTO can be reconstituted in vitro with three purified proteins (KaiA, KaiB, and KaiC) and ATP. These are the only circadian proteins for which high-resolution structures are available. Phase in this nanoclockwork has been associated with key phosphorylations of KaiC. Structural considerations illuminate the mechanism by which the KaiABC oscillator ratchets unidirectionally. Models of the complete in vivo system have important implications for our understanding of circadian clocks in higher organisms, including mammals. The conjunction of structural, biophysical, and biochemical approaches to this system has brought our understanding of the molecular mechanisms of biological timekeeping to an unprecedented level.

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Section: Modeling the In Vitro Oscillatormentioning

confidence: 99%

The Cyanobacterial Circadian System: From Biophysics to Bioevolution

Johnson

Stewart

Egli

2011

Annu. Rev. Biophys.

116

118

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“…In terms of mathematical modeling of the Kai clock, several models have been proposed to reproduce the oscillation of KaiC phosphorylation, among which some have included the kinetics of Kai protein interactions [20] , [21] , [22] , [23] , [24] . These models with Kai protein interactions all capture the periodic dynamics of KaiB-C complexes, but predict that the KaiB-C complex oscillates either leading or in phase with the oscillation of total phosphorylated KaiC, a result that does not seem consistent with available experimental data [13] , [14] , [17] .…”

Section: Introductionmentioning

confidence: 99%

Quantifying the Rhythm of KaiB-C Interaction for In Vitro Cyanobacterial Circadian Clock

Ranganathan

2012

PLoS ONE

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An oscillator consisting of KaiA, KaiB, and KaiC proteins comprises the core of cyanobacterial circadian clock. While one key reaction in this process—KaiC phosphorylation—has been extensively investigated and modeled, other key processes, such as the interactions among Kai proteins, are not understood well. Specifically, different experimental techniques have yielded inconsistent views about Kai A, B, and C interactions. Here, we first propose a mathematical model of cyanobacterial circadian clock that explains the recently observed dynamics of the four phospho-states of KaiC as well as the interactions among the three Kai proteins. Simulations of the model show that the interaction between KaiB and KaiC oscillates with the same period as the phosphorylation of KaiC, but displays a phase delay of ∼8 hr relative to the total phosphorylated KaiC. Secondly, this prediction on KaiB-C interaction are evaluated using a novel FRET (Fluorescence Resonance Energy Transfer)-based assay by tagging fluorescent proteins Cerulean and Venus to KaiC and KaiB, respectively, and reconstituting fluorescent protein-labeled in vitro clock. The data show that the KaiB∶KaiC interaction indeed oscillates with ∼24 hr periodicity and ∼8 hr phase delay relative to KaiC phosphorylation, consistent with model prediction. Moreover, it is noteworthy that our model indicates that the interlinked positive and negative feedback loops are the underlying mechanism for oscillation, with the serine phosphorylated-state (the “S-state") of KaiC being a hub for the feedback loops. Because the kinetics of the KaiB-C interaction faithfully follows that of the S-state, the FRET measurement may provide an important real-time probe in quantitative study of the cyanobacterial circadian clock.

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“…Several studies have indicated that cooperative regulation of ATPase activity in hexameric ATPases is important for their biological functions 19 20 21 22 23 24 . Furthermore, several studies have proposed mathematical models of robust oscillation of KaiC phosphorylation, based on the hexameric structure of KaiC 25 26 27 28 29 30 31 32 33 . The crystal structures of Synechococcus KaiC show that ATP molecules bind at each subunit interface 17 , the autophosphorylation sites face the ATP molecules on the neighbouring protomers 34 and the putative catalytic glutamates of the ATPase motif are at the subunit interface 17 34 .…”

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confidence: 99%

KaiC intersubunit communication facilitates robustness of circadian rhythms in cyanobacteria

et al. 2013

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The cyanobacterial circadian clock is the only model clock to have been reconstituted in vitro. KaiC, the central clock component, is a homohexameric ATPase with autokinase and autophosphatase activities. Changes in phosphorylation state have been proposed to switch KaiC’s activity between autokinase and autophosphatase. Here we analyse the molecular mechanism underlying the regulation of KaiC’s activity, in the context of its hexameric structure. We reconstitute KaiC hexamers containing different variant protomers, and measure their autophosphatase and autokinase activities. We identify two types of regulatory mechanisms with distinct functions. First, local interactions between adjacent phosphorylation sites regulate KaiC’s activities, coupling the ATPase and nucleotide-binding states at subunit interfaces of the CII domain. Second, the phosphorylation states of the protomers affect the overall activity of KaiC hexamers via intersubunit communication. Our findings indicate that intra-hexameric interactions play an important role in sustaining robust circadian rhythmicity.

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Circadian KaiC Phosphorylation: A Multi-Layer Network

Cited by 9 publications

References 48 publications

The Cyanobacterial Circadian System: From Biophysics to Bioevolution

The Cyanobacterial Circadian System: From Biophysics to Bioevolution

Quantifying the Rhythm of KaiB-C Interaction for In Vitro Cyanobacterial Circadian Clock

KaiC intersubunit communication facilitates robustness of circadian rhythms in cyanobacteria

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