ligand ˜ helix of coactivator even when the environmental cues (changes in light and dark) are removed, but the period of this free-running rhythm is generally a little less or more than 24 hours. External signals indicating the time of day cause small adjustments in the running of the clock, so as to keep the organism in synchrony with its environment. Following more drastic shifts, circadian cycles become gradually reset (entrained) by the new cycle of light and dark, as anyone who has experienced jet lag can attest.
We might expect that the circadian clock would be a complex multicellular device, with different groups of cells responsible for different parts of the oscillation mechanism. Remarkably, however, in almost all multicellular organisms, including humans, the timekeepers are individual cells. Thus, a clock that operates in each member of a specialized group of brain cells (the SCN cells in the suprachiasmatic nucleus of the hypothalamus) controls our diurnal cycles of sleeping and waking, body temperature, and hormone release. Even if these cells are removed from the brain and dispersed in a culture dish, they will continue to oscillate individually, showing a cyclic pattern of gene expression with a period of approximately 24 hours. In the intact body, the SCN cells receive neural cues from the retina, entraining the SCN cells to the daily cycle of light and dark; they also send information about the time of day to another brain area, the pineal gland, which relays the time signal to the rest of the body by releasing the hormone melatonin in time with the clock.
Although the SCN cells have a central role as timekeepers in mammals, almost all the other cells in the mammalian body have an internal circadian rhythm, which has the ability to reset in response to light. Similarly, in Drosophila, many different types of cells have a similar circadian clock, which continues to cycle when they have been dissected away from the rest of the fly and can be reset by externally imposed light and dark cycles.
The working of circadian clocks, therefore, is a fundamental problem in cell biology. Although we do not yet understand all the details, studies in a wide variety of organisms have revealed the basic principles and molecular components. The key principle is that circadian clocks generally depend on negative feedback loops. As discussed earlier, oscillations in the activity of an intracellular signaling protein can occur if that protein inhibits its own activity with a long delay (see
Figure 15–65 The activation of nuclear receptors. All nuclear receptors bind to DNA as either homodimers or heterodimers, but for simplicity we show them as monomers. (A) The receptors all have a related structure, which includes three major domains, as shown. An inactive receptor is bound to inhibitory proteins.
Typically, the binding of ligand to the receptor causes the ligand-binding domain of the receptor to clamp shut around the ligand, the inhibitory proteins to dissociate, and coactivator proteins to bind to the receptor’s transcription-activating domain, thereby increasing gene transcription. In other cases, ligand binding has the opposite effect, causing co-repressor proteins to bind to the receptor, thereby decreasing transcription (not shown).
The structure of the ligand-binding domain of the retinoic acid receptor is shown in the absence (left) and presence (middle) of ligand (shown in red). When ligand binds, the blue α helix acts as a lid that snaps shut, trapping the ligand in place. The shift in the conformation of the receptor upon ligand binding also creates a binding site for a small α helix (orange) on the surface of coactivator proteins. (PDB codes: 1LBD, 2ZYO, and 2ZXZ.)
Tim degraded in response to light mRNAs dissociation of heterodimer