Bulletin of the American Physical Society
2008 APS March Meeting
Volume 53, Number 2
Monday–Friday, March 10–14, 2008; New Orleans, Louisiana
Session A7: Oscillations Without Transcription in Vivo and in Vitro |
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Sponsoring Units: DBP GSNP Chair: Michal Zochowski, University of Michigan Room: Morial Convention Center RO5 |
Monday, March 10, 2008 8:00AM - 8:36AM |
A7.00001: Molecular synchronization, the Kai system, and biological oscillators Invited Speaker: In most textbook examples, oscillations in cell biology are driven by the periodic creation and destruction of one or more chemical species. The past few years, however, have seen growing interest in a different sort of oscillator. In these systems, the total concentrations of the major protein components are constant, but the molecules move sequentially through a cycle of different states (e.g. covalent modifications). Macroscopic oscillations appear when the progress of the many individual molecules becomes \textit{synchronized}. The recently-characterized cyanobacterial circadian clock provides a particularly elegant example of such molecular synchronization. Remarkably, with only the 3 proteins KaiA, KaiB, and KaiC, a $\sim$24 hour oscillation in KaiC phosphorylation can be reconstituted \textit{in vitro}. We can thus dissect this biochemical circuit in almost unprecedented detail. Here, we give an overview of the Kai system and its relationship to other oscillators. We begin with a review of the major experimental facts about the Kai system, emphasizing possible mechanisms to synchronize KaiC phosphorylation. We then examine in more detail models in which this synchronization occurs through sequestration of KaiA via \textit{differential affinity}: KaiA, which stimulates KaiC phosphorylation, has a higher affinity for KaiC during certain stages of the phosphorylation cycle; as long as some KaiC molecules at these stages are present in the reaction mixture, they bind all the available KaiA, thereby preventing the other KaiC's from being phosphorylated and proceeding through the cycle. We also discuss the implications of this mechanism for phenomena such as temperature compensation. Finally, we suggest that, in light of lessons learned from the Kai system, a number of other biological oscillators can fruitfully be viewed as examples of molecular synchronization. [Preview Abstract] |
Monday, March 10, 2008 8:36AM - 9:12AM |
A7.00002: Monomer exchange and the hourglass model of protein-based oscillators Invited Speaker: Circadian rhythms in photosynthetic cyanobacteria are under the control of a three protein biochemical network that generates oscillations in the phosphorylation level of one of the proteins. This oscillatory signal has a period of roughly 24 hours and regulates many biological processes in the bacteria to the day and night cycle. The molecular view of the phosphorylation process is that one of the proteins forms a hexameric complex whose phosphorylation levels rise and fall based on the activity of the other two proteins. Each hexameric complex thus functions as an independent molecular clock. However the bacteria contains many such clocks and so how do they interact to generate a coherent oscillating signal? In this talk I will discuss a model that suggests that monomer exchange between hexamers helps to synchronize the population of clocks during the daylight portion of the oscillation. Other synchronizing mechanisms will be highlighted for the other portion of the cycle. Recent experiments will be discussed in light of the exchange model. [Preview Abstract] |
Monday, March 10, 2008 9:12AM - 9:48AM |
A7.00003: Perfect Robust Network Architecture of a Bacterial Circadian Clock Invited Speaker: The circadian core clock of cyanobacteria consists of only three proteins, KaiA, KaiB, and KaiC. The readout of the clock status is given by the phosphorylation level of KaiC hexamers that oszillates with 23h period even under {\it in vitro} conditions. We present a circadian clock model based on mass action kinetics that shows almost perfect agreement with the experimentally found phosphorylation dynamics. The model consists of two feedback loops, with the main oscillatory mechanism realised by a negative feedback via sequestration of the enhancer of KaiC autophosphorylation, that is KaiA. These feedbacks are the reason for the observed outstanding robustness of the KaiABC clock that keeps phase, frequency and amplitude even under concerted serveral fold changes of the Kai protein concentrations. \newline [1] Clodong S. et al, Molecular Systems Biology, (2007) [Preview Abstract] |
Monday, March 10, 2008 9:48AM - 10:24AM |
A7.00004: Stability and Noise in the Cyanobacterial Circadian Clock Invited Speaker: Accuracy in cellular function has to be achieved despite random fluctuations (noise) in the concentrations of different molecular constituents inside and outside the cell. Single cell in vivo monitoring reveals that individual cells generate autonomous circadian rhythms in protein abundance. In multi-cellular organisms, the individual cell rhythms appear to be noisy with drifting phases and frequencies. However, the whole organism is significantly more accurate, the temporal precision being achieved most probably via intercellular coupling of the individual noisy oscillators. In cyanobacteria, we have shown that single cell oscillators are impressively stable and a first estimation rules out strong intercellular coupling. Interestingly, these prokaryotes also have the simplest molecular mechanism at the heart of their circadian clock. In the absence of transcriptional activity in vivo, as well alone in vitro, the three clock proteins KaiA, KaiB and KaiC generate a self-sustained circadian oscillation of autophosphorylation and dephosphorylation. Recent chemical kinetics models provide a possible understanding of the three-protein oscillator, but the measured in vivo stability remains yet unexplained. Is the clock stability a built-in property for each bacterium or does a weak intercellular coupling, make them appear like that? To address this question we first theoretically designed our experiment to be able to distinguish coupling, even weak, from phase diffusion. As the precision of our evaluation increases with the length of the experiments, we continuously monitor, for a couple of weeks, mixtures of cell populations with different initial phases. The inherent experimental noise contribution, initially dominant, is reduced by enhanced statistics. In addition, in situ entrainment experiments confirm our ability to detect a coupling of the circadian oscillator to an external force and to describe explicitly the dynamic change of the mean phase. We report a value of the coupling constant that is small compared to the diffusion constant. These results therefore confirm that the cyanobacterial clock stability is a built-in property: the cyanobacterian clock mechanism is not only the simplest but also the most robust. [Preview Abstract] |
Monday, March 10, 2008 10:24AM - 11:00AM |
A7.00005: Chromosome oscillations in mitosis Invited Speaker: Successful cell division necessitates a tight regulation of chromosome movement via the activity of molecular motors. Many of the key players at the origin of the forces generating the motion have been identified, but their spatial and temporal organization remains elusive. In animal cells, chromosomes periodically switch between phases of movement towards and away from the pole. This characteristic oscillatory behaviour cannot be explained by the current models of chromosome positioning and congression. We perform a self-contained theoretical analysis in which the motion of mono-oriented chromosomes results from the competition between the activity of the kinetochore and chromokinesin motors on the chromosome arms. Our analysis, consistent with the available experimental data, proposes that the interplay between the aster-like morphology of the spindle and the collective kinetics of molecular motors is at the origin of chromosome oscillations, positioning and congression. It provides a natural explanation for the so-called chromosome directional instability and for the mechanism by which chromosomes sense their position in space. In addition, we estimate the in vivo velocity of chromokinesins at vanishing load and propose new experiments to assess the mechanism at the origin of chromosome movement in cell division. [Preview Abstract] |
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