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RESEARCH BRIEFS Collaboration Sheds Light on Assembly Of Cellular Transporter Continuing their work on the structure of clathrin, Tomas Kirchhausen, HMS professor of cell biology at the Center for Blood Research; Stephen Harrison, HMS professor of biological chemistry and molecular pharmacology at Children's Hospital and the Howard Hughes Medical Institute; and Andrea Musacchio, a former postdoctoral fellow in Harrison's lab, have developed a newly detailed view of clathrin-coated vesicles, one of the best understood cellular import machines. Responsible for shuttling into the cell a range of important molecules including LDL cholesterol, clathrin-coated vesicles also play a role in breast cancer through internalization of a key receptor. Their findings, presented in the June Molecular Cell, combine X-ray crystallography data of the clathrin molecule, at 2.6 angstroms, with the cryo-electron microscope view of a clathrin cage, at 21 angstroms, from collaborators in England.     Clathrin, a three-legged pinwheel molecule, forms a lattice of hexagons and pentagons like a soccer ball around the vesicle. The lattice forms with the help of adaptor proteins, making coated pits that grow and pinch off, internalizing receptors on the cell membrane.     After fitting the X-ray data into the electron microscope data, the researchers found that the image of an individual clathrin molecule, or triskelion, is highly puckered, almost resembling an upside-down teacup. It is also a relatively rigid molecule, though there is some amount of flex at the "knees."     To reconcile the rigidity of the individual triskelion with the tightly packed and complicated structure of the coated vesicle, the researchers propose that during assembly and disassembly, the triskelion rotates to lock into position (see image).     The combined structures also gave them a view of the "feet" of clathrin showing that these domains, which bind adaptor proteins and receptors, project into the vesicle at the perfect depth to interact with their cargo.     A Web movie of the vesicle's assembly appears at www.hms. harvard.edu/news/clathrin. —Brief by Justin Yarrow Human Circadian Clock Shown To Keep 24-Hour Time Our internal clocks are more in sync with our wristwatches than previously believed—that's the finding of a team of Brigham and Women's circadian biologists. Charles Czeisler, Jeanne Duffy, Derk-Jan Dijk, and their colleagues have recently discovered that the human circadian pacemaker—the internal clock that controls the rise and fall of body temperature, cortisol, and hormones such as melatonin—cycles, on average, every 24.18 hours. The finding, which appears in the June 25 Science, settles a longstanding controversy.     Plants, insects, mammals, and other animals were known to cycle on a near 24-hour basis, with little variation between individuals. Experiments with humans, on the other hand, suggested that they had a longer average cycle, over 25 hours, and that their cycles could vary anywhere from 13 to 65 hours.     The experiments suffered from a serious flaw, however. Subjects were allowed to turn on lights, even if they were tucked away in caves or windowless labs. Several years ago, Czeisler and his colleagues discovered that ordinary room light can reset the pacemaker.     To avoid the resetting effects of room light and other cues, Czeisler, professor of medicine; Duffy, research fellow in medicine; and Dijk, assistant professor of medicine; and their colleagues tightly controlled their subjects' environment. For about a month, the 24 subjects—11 young men (mean age 24) and 13 older men and women (mean age 67)—were exposed only to very low levels of light, about one tenth that of ordinary room light. To prevent the pattern of light exposure from affecting the subjects' internal clocks, lights were turned on at progressively earlier or progressively later times of the day, essentially creating 20-hour or 28-hour days.     "The point was to decouple extrinsic cues from the internal pacemaker," says Czeisler. Despite the decoupling, body temperature, cortisol, and melatonin levels cycled on an average of every 24.18 hours. And they did so consistently among all subjects, showing the circadian pacemaker is as tightly controlled in humans as in other animals.     The discovery has implications for our understanding not just of sleep disorders, some of which have been attributed to instabilities in the circadian pacemaker, but of the human circadian clock itself. "It's very likely the breakthroughs over the past one to two years regarding the molecular basis of circadian rhythms in other animals apply to human beings as well," says Czeisler. Housekeeping Receptor in Fruit Flies Found When they are not busy fending off foreign invaders, macrophages, the workhorses of the immune system, are responsible for cleaning up debris such as dead cells. Until recently, little was known about how macrophages perform their housekeeping duties in fruit flies. A team of Massachusetts General Hospital researchers has identified the macrophage receptor that is responsible for recognizing apoptotic cells in Drosophila embryos. The receptor, dubbed croquemort (CRQ), is related to a receptor found on mammalian macrophages that is known to recognize dead, or apoptotic, cells.     In fact, the homology to the mammalian CD36 receptor was the first tip that CRQ might be involved in engulfing apoptotic cells. To test the hypothesis, Nathalie Franc, research fellow in dermatology, Kristin White, assistant professor of dermatology, and their colleagues deleted a region of the fly genome that contains the crq gene. Fly embryos were littered with cellular corpses. They tried rescuing flies by reintroducing the crq gene, and the trick worked. "Macrophages were competent to engulf corpses," says White. Moreover, the presence of apoptotic cells appeared to upregulate the CRQ receptor, the researchers report in the June 18 Science.     Intriguingly, flies lacking the crq gene were still able to engulf foreign invaders, such as bacteria. This suggests that macrophages use two different pathways to recognize apoptotic cells and bacteria. The researchers plan to study what surface feature macrophages use to recognize apoptotic cells.     "This is the first engulfment mutant in flies," White says. "It shows flies will be a good model system to study engulfment by professional macrophages." Back to Top