The Journal of Biological Chemistry has recognized Washington University researchers for their work describing the combined structure of two proteins that, when bound together, drive growth of many breast cancers.
Named a paper of the year by the journal, the investigators’ article detailed the structures of proteins that boost the growth of HER2-positive breast cancer. According to senior author Ron Bose, MD, PhD, assistant professor of medicine, understanding the structure of these proteins and how they interact will guide the design of future therapies against HER2-driven cancers.
“Most patients with HER2-positive breast cancer respond very well to current therapies because we know how to target HER2,” said Bose, a medical oncologist at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “In fact, since the introduction of drugs such as Herceptin, patients with HER2-positive breast cancer now have one of the best prognoses. But there are still cases when, for reasons that are unclear, women will die from HER2-positive breast cancer. So although we’ve had a lot of successes, there is still more to learn. And understanding these structures is a step in that direction.”
In many HER2-positive tumors, proteins called HER2 and HER3 come together to drive cancer growth. Understanding how these proteins fit together is crucial to developing better drugs, according to Bose.
Bose also points out that alterations in the HER2 protein are not limited to breast cancer and have been found in many other solid tumors, such as colon, lung, gastric, and head and neck cancers.
Beyond the paper’s importance for cancer treatment, the journal also singled it out because the researchers demonstrated a novel way to determine the structures of proteins, specifically proteins that can’t be crystallized.
“The most common way to study the structures of proteins is to force the protein to form a crystal and take an X-ray picture,” Bose said. “You get beautiful detailed views of it. But some proteins, especially complexes of two or more proteins, fail to form crystals. Having the separate pieces helps, but until you put them together, you don’t know how they will interact. It’s like assembling a complicated jigsaw puzzle without the picture on the front of the box.”
Using a combination of techniques, the researchers analyzed the chemical composition of the proteins and used computer simulations to model how the protein complexes fold, move and interact with water and salt (similar to conditions inside the body).
Bose explained that this study isn’t the first to describe the structures of proteins that don’t form crystals, but he and his colleagues demonstrated that their method is a feasible way to do it.
The Journal of Biological Chemistry (JBC) publishes about 4,000 papers per year and selects 22 papers as the best of the year. The work of Bose and his colleagues was chosen as JBC’s best signal transduction article of 2013.
This work was supported by the National Institutes of Health (NIH) grant numbers R01CA161001, 8P41 GM103422-36, and 2T32HL007088-36; and the National Science Foundation (NSF) grant number DBI 0922879.
Collier TS, Diraviyam K, Monsey J, Shen W, Sept D, Bose R. Carboxyl group footprinting mass spectrometry and molecular dynamics identify key interactions in the HER2-HER3 receptor tyrosine kinase interface. The Journal of Biological Chemistry. August 2013.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
Alvin J. Siteman Cancer Center, the only National Cancer Institute-designated Comprehensive Cancer Center in Missouri, is ranked among the top cancer facilities in the nation by U.S. News & World Report. Comprising the cancer research, prevention and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine, Siteman also is Missouri’s only member of the National Comprehensive Cancer Network.