‘Old chemistry’ helps ISU scientists find new way to study important cell functions

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Amy Andreotti

Going retro isn’t the norm in modern laboratories, yet it helped three Iowa State University researchers discover a new method for scientists to study important functions in living cells.

Amy Andreotti, Bruce Fulton and Qian Xie used “some rather old chemistry” from the 1960s to find an innovative way to monitor structural changes in proteins called kinases, which are found in all cells and have a big say in how they communicate with one another.

The findings are significant. A better understanding of kinase function, which is determined by the shape of its structure, could eventually lead to new drugs and therapies for a variety of diseases including cancer. The new method also can be applied to nearly any kinase of any size, broadening the impact of the ISU research.

Qian Xie

The researchers’ study was recently published in the journal “ACS (American Chemical Society) Chemical Biology.”

Andreotti is a professor in the Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology (BBMB) and Fulton is the manager of ISU’s Biomolecular NMR Facility. Xie, formerly a Ph.D. student on Andreotti’s research team, is now a postdoctoral researcher in chemistry at Princeton University.

“Kinases are one of the main players in all of cellular signaling,” Andreotti said. “Consequently, they have been targets for the development of drugs to control their activity and, therefore, control diseases.”

“Amy’s research can significantly advance the design and development of novel therapeutic strategies for many different types of diseases,” Guru Rao, professor and chair of BBMB, said. “Her cutting-edge work using NMR spectroscopy has revealed new aspects of the structure and activity of kinases that is generally applicable to many kinases.”

The all-important cellular signaling occurs when cells must respond to an external stimulus. When an immune cell, for example, recognizes a virus in the bloodstream, kinases inside the immune cell switch from an inactive to an active state sending the cell’s control center (the nucleus) the signal to combat the infection. Likewise, growth hormones tell kinases to instruct the cell to turn on and grow and divide.

However, problems can arise when the cells remain on when they should turn off. This uncontrolled activity can lead to autoimmune diseases, such as diabetes, multiple sclerosis and rheumatoid arthritis, or lead to cancer.

Because of kinases’ relatively large size, scientists often study their structures with x-ray crystallography. This analytical tool shows kinases in active and inactive states, but not during their critical transition from one state to the other. “We were losing a lot of dynamic information on the intermediate states that kinases can adopt as they shift from active to inactive,” Andreotti said.

Another analytical technique, NMR spectroscopy, hasn’t traditionally been used to study kinases because of their size. Now, however, the ISU researchers have found a way around that. Using a chemical reaction first described in the 1960s, the ISU scientists inserted a special, NMR-active isotope into the kinase at specific locations, allowing them to “see the signals and peek at important parts of the kinase as it transitions between its on and off states,” Andreotti said.

“This technique, while simple on the technical side, is providing a new way to look at how kinases are behaving under a variety of conditions,” she said. “We’re excited about how this new approach may be used by other investigators in the kinase field and how our understanding of these important molecules may be improved as a result.”

BBMB is an academic department jointly administered by ISU’s College of Liberal Arts and Sciences and College of Agriculture and Life Sciences.

Podcast of Andreotti interview with ACS Chemical Biology (See January 2015)

About Liberal Arts and Sciences The College of Liberal Arts and Sciences is a world-class learning and research community. Iowa State’s most academically diverse college, LAS educates students to become global citizens, providing rigorous academic programs in the sciences, humanities and social sciences within a supportive personalized learning environment. College faculty design new materials, unravel biological structures, care for the environment, and explore social and behavioral issues. From fundamental research to technology transfer and artistic expression, the college supports people in Iowa and around the world.

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Contacts: Amy Andreotti, BBMB, 515-294-4953, amyand@iastate.edu Steve Jones, Liberal Arts and Sciences Communications, 515-294-0461, jones@iastate.edu