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!
New study: How does Europe become a leading player for software and IT services?
03.04.2017 | Fraunhofer-Institut für System- und Innovationsforschung (ISI)
Reusable carbon nanotubes could be the water filter of the future, says RIT study
30.03.2017 | Rochester Institute of Technology
Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.
The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
In the race to produce a quantum computer, a number of projects are seeking a way to create quantum bits -- or qubits -- that are stable, meaning they are not much affected by changes in their environment. This normally needs highly nonlinear non-dissipative elements capable of functioning at very low temperatures.
In pursuit of this goal, researchers at EPFL's Laboratory of Photonics and Quantum Measurements LPQM (STI/SB), have investigated a nonlinear graphene-based...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
24.05.2017 | Physics and Astronomy
24.05.2017 | Physics and Astronomy
24.05.2017 | Event News