UT Southwestern Medical Center researchers have taken a major step toward understanding the cellular clock, mapping for the first time the atomic-level architecture of a key component of the timekeeper that governs the body's daily rhythms.
The daily, or circadian, cycles guided by the body's clocks affect our ability to get a good night's sleep, how fast we recover from jet lag, and even the best time to give cancer treatments, said Dr. Joseph Takahashi, senior author of the Science study published online and a pioneer in the study of circadian rhythms.
Understanding the structure of the cellular clock could lead to better treatments for insomnia, diabetes, and even cancer.
"The clock is found in virtually every cell of the body, and is important for controlling many different metabolic functions," said Dr. Takahashi, chairman of neuroscience and a Howard Hughes Medical Institute (HHMI) investigator at UT Southwestern.
Mapping the 3-D structure of the key component in the cellular clock – called the CLOCK:BMAL1 transcriptional activator complex – will have a great impact on the study of circadian rhythms and in other areas like toxicology and the growth of nerve cells, in which proteins in the same family play central roles, he said.
"Ultimately, we have to go to the atomic level to really understand how these proteins work" Dr. Takahashi said.
The Takahashi laboratory has spent years determining the 3-D structure of the CLOCK:BMAL1 complex using X-ray crystallography. The breakthrough came in the spring of 2011 when Yogarany Chelliah, an HHMI research specialist at UT Southwestern, was able to crystallize the proteins. The structure was determined in collaboration with Dr. Hong Zhang, associate professor of biochemistry.The researchers found that the CLOCK protein is tightly wrapped around the BMAL1 protein in an unusually asymmetrical fashion. They identified three distinct areas for interactions between CLOCK and BMAL1 as well as regions for interactions with other molecules that might affect the cellular clock by changing the sleep-wake cycle or other body processes that depend on circadian rhythm, he said.
Dr. Takahashi then used that mouse to identify the world's first circadian rhythm gene in a mammal. Researchers in his laboratory cloned the Clock gene in 1997. In 1998, they discovered that the CLOCK protein worked in concert with the BMAL1 protein in a study done in collaboration with Dr. Charles Weitz at Harvard Medical School.
Two years ago, Dr. Takahashi's team – in collaboration with Dr. Joseph T. Bass at Northwestern University Feinberg School of Medicine in Chicago – reported in Nature that disruptions in the Clock and Bmal1 genes in mice can alter the release of insulin by the pancreas, which results in diabetes.
"We started on this path a long time ago, and it actually began with a mouse, which then allowed us to find the Clock gene, and then from this gene we now see the proteins from their crystal structure," Dr. Takahashi said. "For that to all happen after such a long quest is particularly satisfying."
Other UT Southwestern researchers involved in the study include Nian Huang, postdoctoral researcher in biochemistry; Dr. Yongli Shan, postdoctoral researcher in neuroscience; Clinton A. Taylor, student research assistant; Dr. Seung-Hee Yoo, instructor of neuroscience; and Dr. Carla Green, professor of neuroscience. Dr. Carrie Partch – a former postdoctoral researcher in biochemistry, neuroscience, and the HHMI – is now an assistant professor of chemistry and biochemistry at UC Santa Cruz.
This work was supported by the HHMI, the American Heart Association, and the National Institutes of Health.
This news release is available on our World Wide Web home page at www.utsouthwestern.edu/home/news/index.html
To automatically receive news releases from UT Southwestern via email, subscribe at www.utsouthwestern.edu/receivenews
Deborah Wormser | EurekAlert!
The personality factor: How to foster the sharing of research data
06.09.2017 | ZBW – Leibniz-Informationszentrum Wirtschaft
Europe’s Demographic Future. Where the Regions Are Heading after a Decade of Crises
10.08.2017 | Berlin-Institut für Bevölkerung und Entwicklung
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
21.09.2017 | Physics and Astronomy
21.09.2017 | Life Sciences
21.09.2017 | Health and Medicine