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$4M NIH Grant Supports Synchrotron Work in Protein Structure, Proteomics, and Life Sciences

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This story originally ran on Aug. 25.

By Tony Fong

The Case Western Reserve University School of Medicine last week announced it has been awarded a five-year, $4 million grant from the National Institutes of Health to fund the school's synchrotron center, where, among other things, novel proteomics approaches are being developed.

While synchrotrons have historically been used in chemistry and physics, the life sciences, especially protein-related studies, are increasingly finding value in the technology. The grant, from NIH's National Institute of Biomedical Imaging and Bioengineering, continues a history of funding from the agency to the Case Center for Synchrotron Biosciences stretching back to 1995.

The Case center is based at Brookhaven National Laboratory in Upton, NY, where the National Synchrotron Light Source, built in 1984 and operated by the US Department of Energy, is located.

Worldwide there are about 60 synchrotrons with hundreds of beamline facilities. The Case center is one of six that receives NIH funding.

In the first year of the grant, the center will receive about $1.1 million, and in each of the four remaining years, it will receive about $750,000. In addition to paying for the eight employees at the center and three staffers who provide off-site support from the university in Cleveland, Ohio, the first-year allotment includes funds for the purchase of a new detector for the center's X-ray spectroscopy program for investigations into metal atoms in proteins at low concentrations and molecular structure around the metal, Mark Chance, director of the center, told ProteoMonitor last week.

The funding from the NIBIB supports technology in three technology cores at the Case center — the footprinting core, based on the X28C footprinting beamline, provides facilities for the study of protein and nucleic acid structure and function, including in vivo studies. Mass spec-based research, including novel proteomics approaches invented at the center, are also conducted at this core.

The center also has a macromolecular crystallography core based on the X29 undulating beamline for the study of crystal structures, and the X-ray spectroscopy core, based on the X3B beamline, which is getting the new detector paid for by the grant.

A Future in Proteomics?

A synchrotron is a type of cyclic particle accelerator in which magnetic and electric fields are synchronized to push electrons at speeds approaching the speed of light. Energy is emitted in the form of light, known as synchrotron radiation, which is then used to study the properties of materials.

When the first very large synchrotrons were built more than 60 years ago, most of their users were materials scientists, chemists, and physicists, but increasingly, the life sciences are finding applications for the devices, and today about 40 percent of all synchrotron users worldwide are in the life sciences, according to Chance. That includes research into protein structures, as well as growing applications in proteomics.

Chance was also the director of the center when it operated under the auspices of the Albert Einstein College of Medicine, where he worked before moving to CWRU in 2005.

Today, about 2,200 researchers use the NSLS synchrotron annually, including 550 who use it through the Case center. Research being conducted at the center includes studies focused on new drug design, investigations into fundamental cell processes related to viral infection, cancer, and other diseases.

Chance attributed the growth in life-science synchrotron applications to a number of factors, including improvements in synchrotron technology, dissemination in training, and the general growth in crystallography. About 75 percent of the life science work being conducted with synchrotrons is related to crystallography such as research in protein and nucleic acid structures, Chance said.

Another important element in the growth of the use of synchrotrons in the life sciences was the development of the insertion device, or undulating beamline, "which provided very, very highly columnated, very intense radiation which made a huge leap for the quality of crystallography data and speed at which it can be collected," he said. The undulating beamline, he added, allowed researchers to get structure "out of lousy crystals."

The Case center's X29 undulating beamline was built in 2004 and "it just became hugely popular," Chance said, adding that it is the second most productive beamline in the world now with 400 users.

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As synchrotrons find increasing use in the life sciences, more of them are being built. Since 2006, seven synchrotrons have been commissioned or built in Australia, Asia, and Europe. In the US, a new facility called NSLS II is being constructed at Brookhaven and is scheduled to be completed in 2015. The current grant for the Case center runs through 2014, and if it is renewed, the center will move to the new device, Chance said.

In proteomics, while synchrotrons are still an unexplored technology for the most part, structural biology is increasingly being incorporated into the proteomics workflow and vice versa, which may lead to adoption of synchrotrons in the field.

Structural biologists, Chance said, "are starting to do more complex entities, where it's not a single protein, but multiple proteins in an interaction, and certainly the proteomics community is focused on interactions now and protein complexes. And I think they're starting to cross over a little bit, and we're seeing new technologies where both communities are working together.

"The synchrotron is helping to drive a marriage of these different communities and getting the molecular biology and proteomics communities into thinking more about structure," he said.

In his own research using synchrotrons, Chance is conducting structural proteomics research where data from two complementary workflows are integrated. The first part of the experiment uses the synchrotron to get structural information about a molecule, followed by a proteomics study to get information about the dynamics.

Chance and his colleagues described their work in two recently published studies in the Proceedings of the National Academy of Sciences exploring signal transmission in G-protein coupled receptors. One paper, published in May, offers an analysis of the distribution of water molecules in the transmembrane region of GPCR structures and finds conserved contacts with microdomains that appear to be involved in receptor activation.

Another paper, published Aug. 13, describes novel approaches for the analysis of the structure and dynamics of these water molecules using X-rays to activate the water, and then using mass spectrometry to monitor their positions within the protein structure.

"We're doing crystallography to look at how the receptor signaling process occurs and then we're using this mass spec-based footprinting technology to look at the dynamics of the signal transmission itself, how the signal gets transmitted from one side of the cell membrane to the other and how that varies among different G-protein coupled receptors," said Chance, who is also director of CWRU's Center for Proteomics and Bioinformatics.

As a result of the upgrade to its X-ray spectroscopy core resulting from the $4 million NIBIB grant, the facility will have about five times more sensitivity than the instrument currently installed at the center, putting it on a par with the Stanford Synchrotron Radiation Lightsource.

"There really are only two places in the United States to do this kind of X-ray spectroscopy experiment, and now the East Coast will be as good as the West Coast, if you will," Chance said. "This will allow it to be done on much scarcer lower concentration samples that are more biologically interesting. So it changes the limit of detection dramatically."

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