Using the advanced photon source from the Argonne National Laboratory, researchers determined the structure of an enzyme that plays a key role in the spread of cancer cells.
Chances are, each of us has been touched by cancer in one way or another. Unlike other fatal diseases, cancer can take many forms inside the human body, so knowing more about a single enzyme linked to many types of this disease could lead to more effective treatments.
Researchers using the powerful x-ray beams generated at the Advanced Photon Source (APS), a user facility at the U.S. Department of Energy’s (DOE) Office of Science at the DOE’s Argonne National Laboratory, determined the structure such an enzyme: Taspase1, which plays an essential role in the production of cancer cells in humans.
Tapase1 stimulates the growth and spread of cancer cells in multiple forms of the disease, from childhood leukemia to colon cancer, breast cancer and glioblastoma, which is an aggressive form of cancer of the brain or spinal cord. This new information on the structure of Tapase1 provides a better understanding of how the enzyme may be a target for future cancer treatments.
“The importance of this region of Tapase1 makes it a prime target for the design of inhibitors for cancer therapy.”
– Jose M. Martin-Garcia, Rocasolano Institute of Physical Chemistry
The research team, led by current and former Arizona State University scientists, performed this work at the National Institute of General Medical Sciences and the National Cancer Institute Structural Biology Facility (GM / CA) in APS. The resulting article was published in Structure.
“We have signaled the importance of a previously unobserved fragment of Tapase1 that can be used as an attractive target to inhibit its function,” said lead researcher Jose M. Martin-Garcia, currently at the Rocasolano Institute of Physical Chemistry. in Madrid, Spain. At the time of this research, Martin-Garcia was working in the laboratory of Petra Fromme, professor at Arizona State and co-author of the article.
Tapase1 is a type of enzyme that is initially created as an inactive proenzyme form and then split into parts to generate its active form under the right circumstances.
“This general type of activation takes place in other biological functions, such as digestion and blood clotting,” explained Michael Becker, protein crystallographer in the X-ray science division at Argonne.
For Tapase1, this slicing or cleavage process results in two fragments. Prior to this research, only portions of the structure of Tapase1 and these fragments had been determined. That is, until Martin-Garcia’s team figured out that they could modify the enzyme slightly to join these fragments, creating a loop that allowed the entire functional molecule to crystallize.
The project was not without challenges, however, as explained by Robert Fischetti, life science advisor to the director of APS and group leader at Advanced Photon Source. Fischetti led the design, construction and operation of the National Institutes of Health (NIH) funded beamline series that were used for this research on the structure of Taspase1.
âDetermining the structures of these crystals can be quite difficult,â Fischetti said. âThe capabilities that we have developed at GM / CA have made it possible to collect data of sufficient quality for this research. “
The results were enlightening. The research team discovered that a region of Tapase1 forms a long, spiral-shaped structure that is vital for its function.
âThe crystal structure reported in our article is the first to illustrate Tapase1 in its functionally active state and highlights the critical importance of this spiral-shaped fragment,â said Martin-Garcia. “The importance of this region of Tapase1 makes it a prime target for the design of inhibitors for cancer therapy.”
Martin-Garcia’s research and information on Tapase1 gleaned from Argonne’s APS will help scientists design new treatments focused on Tapase1’s unique structural feature in the fight against cancer.
Reference: âStructural insights into the function of the catalyticly active human Tapase1â by Nirupa Nagaratnam, Silvia L. Delker and Rebecca Jernigan, March 29, 2021, Structure.
DOI: 10.1016 / j.str.2021.03.008
Funding for this research was provided by the National Cancer Institute (NCI); GM / CA at APS was funded by the NCI and the National Institute of General Medical Sciences (both within the National Institutes of Health (NIH)); LS-CAT was funded by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor; APS was funded by the DOE Science Office.