The molecular clockwork of a protein-based circadian oscillator

The circadian clock of the cyanobacterium Synechococcuselongatus PCC 7942 is governed by a core oscillator consisting of the proteins KaiA, KaiB, and KaiC. Remarkably, circadian oscillations in the phosphorylation state of KaiC can be reconstituted in a test tube by mixing the three Kai proteins and adenosine triphosphate. The in vitro oscillator provides a well-defined system in which experiments can be combined with mathematical analysis to understand the mechanism of a highly robust biological oscillator. In this Review, we summarize the biochemistry of the Kai proteins and examine models that have been proposed to explain how oscillations emerge from the properties of the oscillator’s constituents.     

Temporal pattern of LH secretion: regulation by multiple ultradian oscillators versus a single circadian oscillator

The possibility that the 24h rhythm output is the composite expression of ultradian oscillators of varying periodicities was examined by assessing the effect of external continuously or pulsed (20-minute) Gonadotropinreleasing hormone (GnRH) infusions on in vitro luteinizing hormone (LH) release patterns from female mouse pituitaries during 38h study spans. Applying stepwise analyses (spectral, cosine fit, best-fit curve, and peak detection analyses) revealed the waveform shape of LH release output patterns over time is composed of several ultradian oscillations of different periods. The results further substantiated previous observations indicating the pituitary functions as an autonomous clock. The GnRH oscillator functions as a pulse generator and amplitude regulator, but it is not the oscillator that drives the ultradian LH release rhythms. At different stages of the estrus cycle, the effect of GnRH on the expression of ultradian periodicities varies, resulting in the modification of their amplitudes but not their periods. The functional output from the system of ultradian oscillators may superimpose a “circadian or infradian phenotype” on the observed secretion pattern. An “amplitude control” hypothesis is proposed: The temporal pattern of LH release is governed by several oscillators that function in conjunction with one another and are regulated by an amplitude-controlled mechanism. Simulated models show that such a mechanism results in better adaptive response to environmental requirements than does a single circadian oscillator. (Chronobiology International, 18(3), 399-412, 2001)     

LdpA: a component of the circadian clock senses redox state of the cell

The endogenous 24-h (circadian) rhythms exhibited by the cyanobacterium Synechococcus elongatus PCC 7942 and other organisms are entrained by a variety of environmental factors. In cyanobacteria, the mechanism that transduces environmental input signals to the central oscillator of the clock is not known. An earlier study identified ldpA as a gene involved in light-dependent modulation of the circadian period, and a candidate member of a clock-entraining input pathway. Here, we report that the LdpA protein is sensitive to the redox state of the cell and exhibits electron paramagnetic resonance spectra consistent with the presence of two Fe4S4 clusters. Moreover, LdpA copurifies with proteins previously shown to be integral parts of the circadian mechanism. We also demonstrate that LdpA affects both the absolute level and light-dependent variation in abundance of CikA, a key input pathway component. The data suggest a novel input pathway to the circadian oscillator in which LdpA is a component of the clock protein complex that senses the redox state of a cell.     

Control of cyclic chromosome replication in Escherichia coli.

The biochemical basis for cyclic initiation of bacterial chromosome replication is reviewed to define the processes involved and to focus on the putative oscillator mechanism which generates the replication clock. The properties required for a functional oscillator are defined, and their implications are discussed. We show that positive control models, but not negative ones, can explain cyclic initiation. In particular, the widely accepted idea that DnaA protein controls the timing of initiation is examined in detail. Our analysis indicates that DnaA protein is not involved in the oscillator mechanism. We conclude that the generations of a single leading to cyclic initiation is separate from the initiation process itself and propose a heuristic model to focus attention on possible oscillator mechanisms.     

Photoperiodic time measurement in insects: a review of clock models

Based on analyses of responses of insects and mites to a wide range of diel and nondiel experimental light-dark schedules, a variety of models have been developed for the photoperiodic clocks in these species by nearly as many investigators. According to some of these models, the photoperiodic clock is based on a mechanism separate from the circadian system, that is, a so-called "hourglass." According to other models, the clock is based on one or more circadian oscillators that may be coupled to each other and that may or may not show a certain degree of damping. In this context, a rapidly damping oscillator could be regarded as an hourglass. The present article gives an overview of the many different clock models and their philosophies, and it makes comparisons among them to provide a better understanding about how these models are related, if at all, and why the double circadian oscillator model is the most favored model at present.     

The cellular circadian oscillator —A fundamental biological mechanism corresponding to a geophysical periodicity

In correspondence to the geophysical cycle of the solar day, the majority of eucaryotic organisms exhibit the phenomenon of circadian periodicity. This type of biological rhythm is reviewed, mainly as cytological aspects, with regard to the temporal organization of the eucaryote, the question of endogeneity, the occurrence in cells of multicellular organisms, and attempts to explain the molecular mechanism of the basic oscillator.     

Synchronization in a neural network of phase oscillators with the central element

A neural network model is considered which is designed as a system of phase oscillators and contains the central oscillator and peripheral oscillators which interact via the central oscillator. The regime of partial synchronization was studied when current frequencies of the central oscillator and one group of peripheral oscillators are near to each other while current frequencies of other peripheral oscillators are far from being synchronized with the central oscillator. Approximation formulas for the average frequency of the central oscillator in the regime of partial synchronization are derived, and results of computation experiments are presented which characterize the accuracy of the approximation.     

Is nuclear division in Physarum controlled by a continuous limit cycle oscillator?

Analysis of plasmodial fusion experiments shows that the timing of mitosis in the myxomycete Physarum polycephalum is controlled by a discontinuous (extreme relaxation) oscillator. Furthermore, there is no convincing evidence that mitosis and DNA synthesis are “downstream” from the control mechanism.     

松果体昼夜节律生物钟分子机制的研究进展

在各种非哺乳类脊椎动物中 ,松果体起着中枢昼夜节律振荡器的作用。近来 ,在鸟类松果体中相继发现了几种钟基因 ,如Per、Cry、Clock和Bmal等 ,其表达的时间变化规律与哺乳类视交叉上核 (SCN)的非常相似。钟的振荡由其自身调控反馈环路的转录和翻译组成 ,鸟类松果体和哺乳类SCN似乎具有共同的钟振荡基本分子构架 ;若干钟基因产物作为正向或负向调节子影响钟的振荡 ;昼夜性的控时机制同时也需要翻译后事件的参与。这些过程对钟振荡器的稳定性和 /或钟导引的光输入通路有着重要的调控作用     

Recent cyanobacterial Kai protein structures suggest a rotary clock

The cyanobacterial circadian oscillator consists of three Kai proteins, KaiA, KaiB, and KaiC, in its oscillation feedback loop. Structural comparison reveals that the Kai system resembles the F1-ATPase system in which KaiC is equivalent to alpha(3)beta(3), KaiA to gammadelta, and KaiB to its inhibitory factor. It also suggests that there exists a possible haemagglutinin-like spring-loaded mechanism for the activation of KaiA during the formation of Kai complexes.