VTCRI assistant professor Deborah Kelly studies connections on a cellular level
By Susan Trulove
Deborah Kelly studies how we connect – or not – at the tiniest scale. She uses powerful molecular imaging techniques to visualize the dynamic behavior of proteins and how signals are transmitted between and within cells. This work – which includes actually seeing the subunits of proteins -- brings an unprecedented level of resolution to understanding cellular processes.
Widely recognized as one of the leading young biomedical scientists in the important field of structural biology, Kelly is an assistant professor with the Virginia Tech Carilion Research Institute and in the biological sciences department at Virginia Tech with an adjunct appointment in biochemistry at Virginia Tech.
She uses cryo-electron microscopy to slow the movement of molecules and then bombards them with a beam of electrons accelerated by high voltage in a vacuum. It may seem like rough treatment, but she is able to view proteins with a powerful electron microscope as a result of a rapid purification tool she helped develop (See 'Affinity Grid'). The results yield new insights into complex biological machinery, such as the signaling proteins that are found between cells.
“This work is providing new insights into the initial signaling events that occur in normal cellular development, in such cancers as malignant brain tumors, and in normal and pathological development of the heart," said Mike Friedlander, executive director of the Virginia Tech Carilion Research Institute. "Dr. Kelly brings scientific vision, leading edge technology, and a strong computational approach to the study of fundamental life processes in health and in several classes of major diseases. Scientists and physicians at the institute, Virginia Tech, and at Carilion will all benefit from having her as a colleague.”
Understanding the structure of a cell signaling system in action
While a post-doctoral fellow at Harvard Medical School, Kelly and her colleagues did research on the Notch signaling pathway, which links cells to their immediate neighbors. The system is important for cell-to-cell communication. "The Notch signaling pathway … links the fate of a cell to that of the immediate neighbor," the researchers explained in a May 2010 article in PLoS One (Molecular Structure and Dimeric Organization of the Notch Extracellular Domain as Revealed by Electron Microscopy, by Kelly, R.J. Lake, T.C. Middlekoop, H-Y Fan, S. Artavanis-Tsakonas, and T. Walz).
Cell signaling mechanisms control multiple processes affecting a broad spectrum of tissues, cellular fates, and developmental events. "Notch malfunction has been linked to neurovascular abnormalities, cancer, and many congenital syndromes, which means that Notch signaling components are great therapeutic targets in the treatment of diseases," said Kelly.
But first, a good deal more has to be learned about the Notch protein. Researchers determined the primary structure of the Notch receptor decades ago. The large protein spans two cells, binding one to another and releasing molecules that carry important signals to the cell's nucleus. However, detailed biochemical analysis of the functional structure of the Notch protein, with its hundreds of small molecules, has had to wait for the development of new technologies.
Using a very new tool developed by Kelly and colleagues at Harvard only a few years ago, called the Affinity Grid, researchers isolated human Notch receptors and well-understood fruit fly Notch receptors, then analyzed them using electron microscopy and 3D image reconstruction.
They identified where ligands, or linking molecules, bind to the Notch receptor and they discovered that the extracellular portion of the protein – which had never before been seen – is a dimer. That is, it is made of two identical parts. The researchers also observed that the exterior domains of the protein form at least three distinct conformations that look the same in flies and in humans, which may suggest at least three different functional states of the receptor.
"Our electron microscopy analysis revealing that the Notch receptor forms a dimer and adopts distinct conformations now opens the way to correlate the functional state of mutations determined by genetic analyses to the receptor structure," the researchers wrote in the PLoS One article. An important goal for future research is to identify which conformations represent the active and inhibited states of the receptor.