Organisms have developed complex regulatory systems in order to couple metabolism and cell development with changes in their environment. Such adaptation is well demonstrated by circadian clocks, which synchronize cellular responses to the diurnal light cycle. Due to their central role in pacing metabolism, biological clocks impact many aspects of human physiology, behavior and the treatment of disease. Although genetics and cell biology have made great progress in understanding the function of clock genes, the molecular mechanisms that compose the underlying transcriptional feedback loops, and their light entrapment, remain largely unknown. Primary photoreceptors and their targets have been identified in eukaryotic model systems such as Neurospora, (filamentous fungi) and Drosophila (flies). Preliminary characterization of light-sensors white collar 1 (WC-1) and vivid (WD) from Neurospora and cryptochrome (CRY) from Drosophila, has defined structures and reactivities that implicate both flavin photochemistry and thiolate redox chemistry in the activation of Per-Arnt-Sim (PAS) domain-containing transcription factors. Crystallographic and spectroscopic characterization of how large-scale protein conformational changes propagate from cofactor photochemistry to generate complex alterations in protein/protein interactions will provide a molecular understanding for clock function. Studies of circadian clock proteins have been hampered by the complexity of the cellular responses, the presence of multiple entrainment mechanisms, and the lack of structures for key proteins. High-resolution structures of these photoreceptors in various states of activation and in complex with their downstream partners will delineate individual residues important for cellular reactivity. Both in vivo and in vitro analysis of variant clock proteins designed to decouple their properties will help fragment entrainment pathways and identify additional levels of clock control, such as response to cellular redox potentials. Parallel investigations of related mammalian clock proteins will reveal mechanisms of action that will aid in the prediction and perturbation of function. Ultimately, such studies of clock proteins will provide a molecular description of behavior that promises advancements in the treatment of mental disorders and many other maladies.
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