October 1, 2018

Cornell Lab Discovers New Regulatory Mechanism of Protein, Sheds Light on Importance of Cornell’s High Energy Synchrotron Source

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Proteins are strikingly complex macromolecules, which control every aspect of molecular function in all living organisms, making them an interesting research target. The Ando Lab studies the structure of proteins, specifically enzymes, in order to understand their function, using structural techniques like x-ray diffraction and small-angle x-ray scattering. These techniques allow for the visualization of atomic and molecular structure of proteins.

Small-angle x-ray scattering is a technique used to study the structure of proteins in solution. SAXS maintains an advantage over other techniques because it allows for the understanding of the movement of proteins; however a caveat to SAXS is its lower resolution, creating the need for combinatorial approaches to studying proteins such as combining SAXS with chromatography.

In their newest publication, “An endogenous dAMP ligand in Bacillus subtilis class Ib RNR promotes assembly of a noncanonical dimer for regulation by dATP”, published in Proceedings of the National Academy of Sciences of the United States of America, collaborators of the Ando Lab studied the crystal structure of a protein and discovered that the protein was interacting in a way that they hadn’t seen before. X-ray crystallography revealed the protein was forming a new dimer: a molecular complex that consists of two identical molecules linked together.

“The problem with crystals is that it is a packing structure of proteins stacked one on top of the other and that’s not really physiological,” said Will Thomas, a fourth year graduate student in the Ando Lab. To address this issue, the Ando lab was able to use SAXS as a complementary technique to confirm that the same structure was forming in solution.

Thomas talked about the unique chemical properties of proteins.

“When we think of proteins, we often think of enzymes which are considered to be catalysts. However, they are not just catalysts: proteins are also really good at performing the chemistry only when they’re supposed to,” Thomas said.

Thomas discussed how even the most basic forms of life, like bacteria, have to be in control of when they are doing certain reactions and what products they are forming. In humans, these regulatory mechanisms are important in preventing cancer.

“Many of the proteins we study are drug targets, so if you can understand how proteins are naturally regulated, then you can also understand how to develop drugs to artificially regulate them,” Thomas said.

An integral component to the Ando Lab’s research is the Cornell High Energy Synchrotron Source. CHESS is the only synchrotron source in the U.S. that has been funded historically by the National Science Foundation and is on Cornell’s Ithaca campus.

“CHESS has a certain culture where they really try to educate and nurture users in addition to doing a lot of innovation and synchrotron science: many of the students who use CHESS end up becoming very good at x-ray work,” said Prof. Nozomi Ando, chemistry and chemical biology, who is the principal investigator of the Ando Lab.

In this sense, CHESS can be viewed as not only a research tool but also an education tool. “That mentality of education lends itself to being more open to exploring ideas and gives more freedom to the experimenter,” said Gabrielle Illava ’17, who is a second year graduate student in the Ando lab. Illava came to Cornell as a junior transfer and began working with Prof. Sol Grunner, physics, who was the former director of CHESS. Illava described the environment at CHESS as an undergraduate as “inherently collaborative” and credits the support she received at CHESS with helping shape her as a scientist.

“It’s really rare for a synchrotron to welcome undergraduates throughout the year to do experiments, so we would be losing that if CHESS were to go away” said Ando. CHESS’s funding situation has changed over time: now the accelerator is operated solely for the benefit of x-ray users. Accelerator operations are expensive and usually require a lot of energy, especially for cooling helium.

“CHESS was originally operating as a high-energy physics facility and then the x-ray work was sort of parasitic on that operation,” said Steve Meisburger Ph.D. ’14 who is a postdoctoral fellow in the Ando Lab.

“The NSF would not like to be the sole steward of CHESS and is looking to share the financial burden with other partners. The challenge for now is locating other partners who can support the facility and keep it going,” said Meisburger.

According to current CHESS director Prof. Joel Brock, applied and engineering physics, CHESS is currently in the last six months of its five year operating award from the National Science Foundation.

Every five years CHESS must submit a proposal to operate for the next five years. The NSF has an internal review process that takes almost two years to complete. If the NSF decides to go forward, the NSF then negotiates a new cooperative agreement with Cornell. Thus, CHESS must regularly demonstrate that it is the best use of the taxpayers money.

“We do a tremendous job of running a world-class synchrotron facility with just a fraction of the operating budgets of other leading facilities,” said Brock.

CHESS’s other government supporters include the National Institutes of Health, the Office of Naval Research, the Air Force Research Laboratory, and New York State for the current capital upgrade project called CHESS-U. CHESS-U is an upgrade that will rebuild the Cornell Electron Storage Ring to improve its performance as an x-ray source, according to Brock.

“When CHESS-U concludes in early 2019, CHESS will be one of five third generation, high-energy synchrotron sources in the world, and one of only two in the U.S., making CHESS a premiere destination for researchers from around the world,” said Brock. CHESS-U construction is finishing on Nov. 1, and tours of the upgraded facility will be available starting Nov. 13.

“The future of CHESS is going to be amazing,” said Brock. “For the past several years CHESS has been able to compete exceptionally well on the international stage despite being an aging source. Every decade or so, facilities need to upgrade to remain international leaders. CHESS-U is doing that for CHESS. CHESS is now poised to be a world-leading synchrotron facility for the foreseeable future.”