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3D Structure of Telomerase Mapped

By BiotechDaily International staff writers
Posted on 22 Apr 2013
Image: The three-dimensional electron microscopy structure of the complete Tetrahymena telomerase enzyme complex, with previously solved high-resolution structures modeled in (Photo courtesy of Jiansen Jiang, Edward Miracco/UCLA chemistry and biochemistry departments).
Image: The three-dimensional electron microscopy structure of the complete Tetrahymena telomerase enzyme complex, with previously solved high-resolution structures modeled in (Photo courtesy of Jiansen Jiang, Edward Miracco/UCLA chemistry and biochemistry departments).
For the first time, scientists have resolved the mystery of how the various parts of a complete telomerase enzyme fit together and function in a three-dimensional (3D) structure.

The creation of the first complete visual map of the telomerase enzyme, which is known to play a significant role in aging and most cancers, represents an advance that could open up a host of new approaches to fighting disease, according to the scientists. “Everyone in the field wants to know what telomerase looks like, and there it was. I was so excited, I could hardly breathe,” said Dr. Juli Feigon, a University of California, Los Angeles (UCLA; USA) professor of chemistry and biochemistry and a senior author of the study. “We were the first to see it.”

The scientists reported each component’s positions of the enzyme in relation to one another and the entire organization of the enzyme’s active site. In addition, they demonstrate how the different components contribute to the enzyme's activity, uniquely linking structure with biochemical function.

The study’s findings were published April 11, 2013, in the print edition of the journal Nature. “We combined every single possible method we could get our hands on to solve this structure and used cutting-edge technological advances,” said co-first author Dr. Jiansen Jiang, a researcher who works with Dr. Feigon and the study’s co-senior author, Z. Hong Zhou, director of the Electron Imaging Center for Nanomachines at the California NanoSystems Institute at UCLA and a professor of microbiology, immunology and molecular genetics. “This breakthrough would not have been possible five years ago.”

“We really had to figure out how everything fit together, like a puzzle,” said co-first author Dr. Edward Miracco, a US National Institutes of Health (Bethesda, MD, USA) postdoctoral fellow in Dr. Feigon’s laboratory. “When we started fitting in the high-resolution structures to the blob in Dr. Feigon’s laboratory. “When we started fitting in the high-resolution structures to the blob that emerged from electron microscopy, we realized that everything was fitting in and made sense with decades of past biochemistry research. The project just blossomed, and the blob became a masterpiece.”

Whereas most cells have comparatively low levels of telomerase, 80%–90% of cancer cells have abnormally high telomerase activity. This prevents telomeres from shortening and extends the life of these tumorigenic cells—an important contributor to cancer progression. The new findings has huge potential for drug development that takes into account the way a drug and target molecule might interact, given the shape and chemistry of each component. Until now, designing a cancer-fighting drug that targeted telomerase was much like shooting an arrow to hit a bulls-eye while wearing a blindfold. With this complete visual map, the researchers are starting to remove that blindfold.

“Inhibiting telomerase won’t hurt most healthy cells but is predicted to slow down the progression of a broad range of cancers,” said Dr. Miracco. “Our structure can be used to guide targeted drug development to inhibit telomerase, and the model system we used may also be useful to screen candidate drugs for cancer therapy.”

The researchers solved the structure of telomerase in Tetrahymena thermophila, a one-cell eukaryotic organism in which scientists first identified telomerase and telomeres, leading to the 2009 Nobel Prize in medicine or physiology. Research on Tetrahymena telomerase in the lab of co-senior author Dr. Kathleen Collins, a professor of molecular and cell biology at the University of California (UC), Berkeley (USA), laid the genetic and biochemical foundation for the structure to be solved.

“The success of this project was absolutely dependent on the collaboration among our research groups,” said Dr. Feigon. “At every step of this project, there were difficulties. We had so many technical hurdles to overcome, both in the electron microscopy and the biochemistry. Pretty much every problem we could have, we had, and yet at each stage these hurdles were overcome in an innovative way.”

One of the biggest surprises, the researchers said, was the role of the protein p50, which acts as a hinge in Tetrahymena telomerase to allow dynamic movement within the complex; p50 was found to be an essential player in the enzyme’s activity and in the recruitment of other proteins to join the complex. “The beauty of this structure is that it opens up a whole new world of questions for us to answer,” concluded Dr. Feigon. “The exact mechanism of how this complex interacts with the telomere is an active area of future research.”

Related Links:

University of California, Los Angeles
University of California, Berkeley



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