The three-dimensional electron microscopy structure of the complete Tetrahymena telomerase enzyme complex, with previously solved high-resolution structures modeled in. (Credit: Jiansen Jiang, Edward Miracco/UCLA Chemistry and Biochemistry)
The picture above shows the power of multi-disciplinary collaboration aided by the power of the Internet and the cloud. A new example arose over the last three weeks as two different groups of researchers from multiple countries and disciplines published papers showing that they had mapped the structure of telomerase, and the second set of researchers visualized its structure, as shown above.
These results are pretty close to a moonshot for molecular biologists. The significance arises because telomerase is the protein understood to provide immortal life to stem cells. Perhaps that’s at least part of why one of the first to see telemorase is quoted as saying: " I was so excited I could hardly breathe."
Cancer researchers also are excited. Why? Because most types of cancer cells hijack the telomerase protein to create their own immortality. Some also see telomerase as the cellular fountain of youth. That label is applied because it regulates the life of chromosomes. By regulating chromosomes, the protein is thought to hold a significant role in aging.
Why do the structures matter? Drug discovery is less prone to failure when the protein structures are known and visualized. New doors just opened.
The new and collaborative findings arrived through work that it is said could not have been accomplished as recently as five years ago. And the research derived outcomes from thousands of contributors, as highlighted by the quotes below.
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"Mapping the cellular fountain of youth — telomerase. This is one of the results of a major research project involving more than 1,000 researchers worldwide, four years of hard work, DKK 55 million from the EU and blood samples from more than 200,000 people. This is the largest collaboration project ever to be conducted within cancer genetics."
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"A gene is like a country. As you map it, you can see what is going on in the various cities. One of the cities in what could be called Telomerase Land determines whether you develop breast cancer or ovarian cancer, while other parts of the gene determine the length of the telomeres. Mapping telomerase is therefore an important step towards being able to predict the risk of developing different cancers. In summary, our findings are very surprising and point in many directions. But as is the case with all good research, our work provides many answers but leaves even more questions," says Stig E. Bojesen.
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"We really had to figure out how everything fit together, like a puzzle," said co-first author Edward Miracco, a National Institutes of Health postdoctoral fellow in 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."
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While most cells have relatively low levels of telomerase, 80 percent to 90 percent of cancer cells have abnormally high telomerase activity. This prevents telomeres from shortening and extends the life of these tumorigenic cells — a significant contributor to cancer progression.
The new discovery creates tremendous potential for pharmaceutical 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 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, the single-celled 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 Kathleen Collins, a professor of molecular and cell biology at UC Berkeley, laid the genetic and biochemical groundwork for the structure to be solved.
"The success of this project was absolutely dependent on the collaboration among our research groups," said Feigon.
"At every step of this project, there were difficulties," she added. "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," Feigon said. "The exact mechanism of how this complex interacts with the telomere is an active area of future research."
This research was funded by the National Science Foundation and the National Institutes of Health.
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