Circadian (daily) rhythms are ubiquitous regulatory functions, found in organisms from bacteria to mammals, that control various biological activities including behavior, metabolism, and gene expression. Circadian clock systems can be found in evolutionarily diverse eukaryotes, including insects, plants, fungi and mammals, and have been demonstrated in a single prokaryotic group, the cyanobacteria (see Ref #1 and #2). In general, proteins from different circadian clock systems have little sequence similarity.

Circadian clock function can be modeled as having three common constituents: input pathways, a central oscillator, and output pathways (for the review, see Ref #2 and Diagram). Light and temperature are the environmental stimuli recognized most commonly to act through input pathways to synchronize the phase of the circadian rhythm with environmental cycles. The central oscillator generates and sustains an oscillation that has an approximately 24-h period. The endogenous circadian oscillation is coupled to clock-controlled processes through output pathways.

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(1) - organisms where KaiA is not found ( as in all Prochlorococcus marinus subsp.);

(2) - organisms where the major timekeeping complex ( KaiA, KaiB and KaiC ) is complete, but some of Input pathways proteins is absent ( as in Synechocystis sp. PCC 6803);

(3) - organisms with the complete set of Circadian clock ( as in Nostoc punctiforme);

(-1) - organisms without any known Circadian clock core components ( as in Gloeobacter violaceus PCC 7421);

Input pathways - proteins CikA, Pex and LdpA - set the clock to local time each day:
The only component known to be involved in an input pathway for resetting the clock is the histidine protein kinase CikA, which belongs to the bacteriophytochrome family of proteins (see Ref #4 and #5).
CikA (754 aa) is a typical histidine protein kinase that carries the expected motifs for this class of proteins. However, other signatures in the protein are somewhat atypical. Upstream of the kinase domain is a GAF motif, similar to the bilin-binding domains of the bacteriophytochrome class of photoreceptors. However, CikA lacks the Cys and His residues that provide covalent linkage to the chromophore, and CikA purified from the cyanobacterium does not carry a covalently attached bilin. CikA will bind phytochromobilin and phycocyanobilin in vitro, but the adduct is not photoactive. The domain appears to be regulatory because its removal strongly suppresses in vitro autophosphorylation activity of the kinase. Kinase activity is stimulated by elimination of a receiver-like domain near the amino terminus. This domain is likely to be an example of a pseudo-receiver.
In addition to the CikA histidine protein kinase LdpA (an FeS protein) and Pex (period extender) are thought to be input elements.
Pex may be a modifier of the circadian clock, while at the same time its expression is controlled by the circadian clock and therefore by clock gene cluster kaiABC. Disruption of pex gene shortens the circadian period and overexpression lengthens the period. An extra copy of the pex gene extends the circadian period by about 2 h (Ref. #6). No pex homolog was found in the whole genome of the cyanobacterium Synechocystis sp. strain PCC 6803.
Resently, the sulfur protein LdpA was identified as a new component of an input pathway to the cyanobacterial clock ( Ref. #7). LdpA protein carries iron-sulfur cluster-binding motifs. Disruption of ldpA significantly attenuated the ability of S. elongatus to modulate the FRP under different light intensities. It is suggested that the circadian clock is modulated by the redox state in cyanobacteria, acting at least in part through the iron.

The major timekeeping complex - KaiA, KaiB and KaiC - circadian oscillator:
All three Kai proteins interact homotypically and heterotypically with each of the other two (see Ref. #8). During the course of a light/dark cycle (and also in continuous light after entrainment by such a cycle), the Kai proteins are found in complexes of various sizes. The KaiC hexamer is prevalent at many times, but in the late night all three Kai proteins and SasA are in a high molecular weight complex, presumably together. Over such a time course the abundance of KaiC and its phosphorylation state oscillates. KaiB abundance oscillates in a pattern similar to KaiC, but KaiA fluctuations are damped in amplitude relative to the other two proteins.
. Disruption of any individual kai gene abolishes circadian rhythms, suggesting that these genes are central to the timing mechanism . None of the Kai proteins (KaiA, KaiB, or KaiC) shares sequence similarity with any eukaryotic clock protein. The kai genes are ubiquitous among cyanobacteria, with probable kaiC sequence identified in forty phylogenetically diverse species. kaiA is the most sequence-diversified of the kai genes, as only four are identifiable via sequence comparisons. Curiously, the Synechocystis sp. strain PCC 6803 genome, which contains multiple kaiB and kaiC genes, has only one kaiA gene. Apparent homologues of kaiB and kaiC are found among noncyanobacterial eubacteria and the archaea. However, the kaiA gene appears confined within the cyanobacteria, which are the only prokaryotes with demonstrated circadian rhythms.

Output pathways – SasA, CPM and PSF - relay temporal information to downstream genes.
SasA, a clock-associated histidine kinase, is necessary for robustness of the circadian rhythm of gene expression and implicated in clock output. The N-terminal domain of SasA (N-SasA) interacts directly with KaiC and likely functions as the sensory domain controlling the SasA histidine kinase activity. N-SasA and KaiB share significant sequence similarity and, thus, it has been proposed that they would be structurally similar and may even compete for KaiC binding. The simplest hypothesis is that SasA physically interacts with the oscillator and relays temporal information to downstream genes (Ref. #9).
CPM (circadian phase modifier) is involved in an output pathway of the circadian clock. Mutation of cpmA altered the phasing of the circadian rhythm for a subset of genes. It is surprising that the cpmA mutation dramatically changed the phase of the kaiA expression rhythm but had a very minor effect on the phase of the kaiB expression rhythm (Ref. #10).
PSF (group 2 RNA polymerase sigma factors). Inactivation of any of the four known group 2 sigma factor genes (rpoD2, rpoD3, rpoD4, and sigC), singly or pairwise, affects circadian properties of a subset of reporter genes, suggesting that the combinatorial action of sigma factors contributes to wild-type circadian rhythmicity (Ref. #11).

=============References========================

1. V. Dvornyk, O. Vinogradova and E. Nevo, Origin and evolution of circadian clock genes in prokaryotes, Proc. Natl Acad. Sci. USA 100 (2003), pp. 2495–2500. PMID: 12604787

2. Lorne J, Scheffer J, Lee A, Painter M, Miao VP. Genes controlling circadian rhythm are widely distributed in cyanobacteria. FEMS Microbiol Lett. 2000 Aug 15;189(2):129-33.

3. Golden SS. Timekeeping in bacteria: the cyanobacterial circadian clock. Curr Opin Microbiol. 2003 Dec;6(6):535-40. Review.

4. Mutsuda M, Michel KP, Zhang X, Montgomery BL, Golden SS. Biochemical properties of CikA, an unusual phytochrome-like histidine protein kinase that resets the circadian clock in Synechococcus elongatus PCC 7942. J Biol Chem. 2003 May 23;278(21):19102-10.

5. Schmitz, O., M. Katayama, S. B. Williams, T. Kondo, and S. S. Golden. CikA, a bacteriophytochrome that resets the cyanobacterial circadian clock. Science. 2000, 289:765-768.

6. Kutsuna, S., T. Kondo, S. Aoki, and M. Ishiura. A period-extender gene, pex, that extends the period of the circadian clock in the cyanobacterium Synechococcus sp. strain PCC 7942. J. Bacteriol., (1998), 180:2167-2174.

7. Katayama, M., T. Kondo, J. Xiong, and S. S. Golden. IdpA encodes an iron-sulfur protein involved in light-dependent modulation of the circadian period in the cyanobacterium Synechococcus elongatus PCC 7942. J. Bacteriol. (2003), 185:1415-1422.

8. H. Kageyama, T. Kondo and H. Iwasaki, Circadian formation of clock protein complexes by KaiA, KaiB, KaiC and SasA in cyanobacteria. J. Biol. Chem. 278 (2003), pp. 2388–2395

9.V. Dvornyk, H.-W. Deng, and E. Nevo. Structure and Molecular Phylogeny of sasA Genes in Cyanobacteria: Insights into Evolution of the Prokaryotic Circadian System
Mol. Biol. Evol. (2004); 21(8): 1468 - 1476.

10. Katayama, M., N. F. Tsinoremas, T. Kondo, and S. S. Golden. cpmA, a gene involved in an output pathway of the cyanobacterial circadian system. J. Bacteriol. (1999) 181:3516-3524.

11. Nair U, Ditty JL, Min H, Golden SS. Roles for sigma factors in global circadian regulation of the cyanobacterial genome. J Bacteriol. 2002 Jul;184(13):3530-8.

12. Johnson CH. Bacterial circadian programs.Cold Spring Harb Symp Quant Biol. 2007;72:395-404. Review.PMID: 18419297

13. Dvornyk V, Knudsen B. Functional divergence of the circadian clock proteins in prokaryotes.
Genetica. 2005 Jul;124(2-3):247-54. PMID: 16134337