Tesmer lab determines full-length structure of a cardiovascular protein
Researchers at the Life Sciences Institute (LSI) have illustrated how a protein activates an enzyme in heart cells in response to a hormonal stimulus. These interactions help regulate calcium levels in the cardiovascular system, where changes in calcium can cause cardiac hypertrophy and heart failure.
Their findings, published electronically Feb 3. in Nature Structural and Molecular Biology, point the way to possible treatments for cardiovascular disease.
Using a powerful combination of techniques, researchers in the lab of John Tesmer, LSI faculty member, and in the lab of Georgios Skiniotis, also a faculty member in the LSI, obtained the first images of the full-length protein phospholipase C b3 bound to its activating protein, Gaq. This signaling pathway is initiated by hormones binding to G protein-coupled receptors, a class of receptors that cause cells to respond to diverse stimuli, including light and neurotransmitters. When Gaq is activated in response to a hormone, it binds to phospholipase C b at several sites.
The researchers used a combination of X-ray crystallography, a technique for visualizing the structure of protein molecules by exposing protein crystals to X-rays, and electron cryo-microscopy to create 3D reconstructions of how phospholipase C b3 and Gaq interact in solution.
“Phospholipase C b is very large and very flexible,” said Angeline Lyon, American Heart Association Post-Doctoral Fellow in the Tesmer lab. Its size and unusual shape presented many practical challenges during the structure determination process. “When Dr. Tesmer suggested we crystallize the whole thing, I thought he was crazy, but we were lucky,” she said.
John Tesmer is a research professor in the Life Sciences Institute, where his laboratory is located and all his research is conducted. He is also a professor of biological chemistry and pharmacology at the University of Michigan Medical School.