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Scientists Model 3D Structures of Body Clock-controlling Proteins

by VR Sreeraman on  April 12, 2009 at 12:46 PM Research News   - G J E 4
 Scientists Model 3D Structures of Body Clock-controlling Proteins
Scripps Research scientists say that they have determined the molecular structure of a plant photolyase protein, which is very similar to the two proteins that control the circadian clock in humans and other mammals.
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The researchers claim that their study has even enabled them to test how structural changes affect the function of such proteins.

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"The plant photolyase structure provides a much better model to use to study how the cryptochrome proteins in the human clock function than we have ever had before," says Dr. Kenichi Hitomi, a postdoctoral research fellow at Scripps Research.

"It's like knowing for the first time where the engine is in a car. When you know what the most important parts of the protein are, then you can begin to figure out how it functions," the researchers added.

Dr. Elizabeth Getzoff, professor in the Department of Molecular Biology and member of The Skaggs Institute for Chemical Biology at Scripps Research, says that understanding how these proteins work may be helpful in fixing the clock when needed.

"In addition to decoding how the clock works, a long-term goal is to develop a drug to help people who can't reset their clock when they need to, like people who work night shifts or travel long distances. Having the three-dimensional protein is a great step forward in both of those pursuits," she says.

Working in collaboration with researchers from Scripps Research and from other institutions, including two universities in Japan, Hitomi studied Arabidopsis thaliana, a plant native to Europe and Asia that has one of the smallest genomes of all plants.

The researchers point out that just like all other plants, this plant also contains proteins known as photolyases, which use blue light to repair DNA damage induced by ultraviolet light.

They say that humans and mammals possess a homologous protein known as cryptochrome that modulates the circadian clock.

Getzoff says: "This is an amazing, and very puzzling, family of proteins, because they do one thing in plants and quite a different thing in mammals, yet these cousins all have the same structure and need the same cofactor, or chemical compound, to become activated."

Hitomi adds: "All of these proteins were probably originally responses to sunlight. Sunlight causes DNA damage, so plants need to repair this damage, and they also need to respond to sunlight and seasons for growth and flowering. The human clock is set by exposure to sunlight, but also by when we eat, sleep, and exercise."

Hitomi and his colleagues set about producing proteins from the Arabidopsis thaliana genes that produce two related photolyase enzymes. These genes had been cloned earlier in the laboratory of co-author Dr. Takeshi Todo of Kyoto University.

The researchers moved the gene from the plant into E. coli bacteria to produce a lot of the protein, and later crystallized it to determine the atomic structure by using X-ray diffraction.

The researchers then produced a variety of mutant proteins in order to test the functional structure of the enzymes.

"We can now look at things that are the same and different between human and mouse cryptochromes and plant photolyases. Our results provide a detailed, comparative framework for biological investigations of both of these proteins and their functions," says Hitomi.

He believes that his team's findings may form the basis of drugs that can ease jet lag and regulate drug metabolism, as well as help better understand some fascinating circadian clock disorders that have been found in mice and man.

The study has been published in The Proceedings of the National Academy of Sciences (PNAS).

Source: ANI
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