A team of scientists at the Virginia Tech Carilion Research Institute developed a new technique to provide the first three-dimensional view of a protein that can cause breast cancer.
The results were published this week in the Nature Partner Journal, Breast Cancer.
“Mutations can change protein function at the molecular level,” said Deborah Kelly, an assistant professor at the Virginia Tech Carilion Research Institute and lead author on the study. “Many diseases, including breast cancer, are related to mutations that alter protein structure, but studying those changes is difficult without the use of new visualization tools.”
The breast cancer susceptibility protein, BRCA1, monitors for errors in DNA and corrects the mistakes during replication. When the protein is mutated, its ability to correct DNA errors is hindered, which can lead to cancer.
Many women who discover they carry a mutated BRCA1 gene often undergo drastic preventive surgery to limit their chances of developing breast cancer.
“There are several different types of breast cancer, and some are more difficult to treat than others,” Kelly said. “Part of the problem is that we do not fully understand how cancer-related proteins operate in health or in disease. That’s what we’re trying to address.”
Kelly and her team developed a “tunable” microchip that can capture proteins from human breast cancer cells to view them with high precision and to study how they function and interact with other molecules.
“This technical breakthrough allowed us to perform the first side-by-side comparison of healthy and mutated BRCA1 complexes in 3-D,” Kelly said. “In turn, these insights revealed new information about how these tumor-related proteins operate in healthy and diseased situations.”
The scientists flash-froze the molecular assemblies to image the structures at high resolution using cryo-electron microscopy. They used computational methods to analyze the contents of the microchips in precise detail and reconstruct an accurate spatial representation of the protein’s atomic structure.
“The structural changes Dr. Kelly and her team observed clarify how BRCA1 interacts with specific biological complexes and have important implications for understanding how BRCA1 can influence cancer,” said W. Gray Jerome, an associate professor and the director of the graduate program in cellular and molecular pathology at the Vanderbilt University School of Medicine, who was not a part of the research team. “Direct observation of this biological complex has clarified a number of issues involved in how BRCA1 influences DNA repair, a process important in protections from cancer, and has also identified several exciting avenues for further exploration.”
Kelly’s microchip method can, in theory, be used to study specific interactions in many diseases, and the precision of imaging in cancer-specific assemblies has led Kelly to develop the new line of investigation, termed structural oncology.
“In a broader sense, our combined structural and biochemical approaches provide a unique opportunity to investigate native protein interactions related to both normal and diseased processes,” Kelly said. “This new approach may help shed light on the inner-workings of native proteins in a unique way that has not been fully explored in human cancer research.”
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