The inner workings of a crucial protein involved in a variety of biological functions have been identified by researchers, potentially opening the way for more effective and less harmful cancer treatments.
The researchers discovered how the tankyrase protein turns itself on and off by self-assembling into 3D chain-like structures using Nobel Prize-winning imaging techniques.
Their research, which was published in the journal Nature, offers a critical structural understanding of the mysterious but significant tankyrase protein, which is particularly key in assisting with the development of bowel cancer.
The Institute of Cancer Research in London hopes that their research will lead to the development of novel cancer therapies that can control tankyrase more effectively and with fewer side effects than is currently possible.
The key finding might affect the treatment of numerous malignancies, diabetic, inflammatory, cardiac, and neurodegenerative illnesses, among other conditions.
Cancer Research UK, Wellcome, and the Institute of Cancer Research (ICR), which is both a charity and a research organization, provided the majority of the study’s funding.
In order for the body to maintain stem cells and perform functions like cell division and development, an enzyme called tankyrase is necessary. However, when Wnt signaling is out of control, it can, among other things, promote bowel cancer. Tankyrase is also in charge of other essentials for preventing cancerous cell processes, like telomere maintenance.
Tankyrase, a member of the same “PARP family” of proteins, is still not fully understood. Even while medications that target PARP1 have already reached the clinic, researchers are still unsure of how tankyrase is activated, how it works, or how to stop it without having undesirable side effects.
The activation mechanisms of tankyrase and PARP1 are compared for the first time in this study. They propose that, like PARP1, tankyrase functions by being drawn to a particular location and “self-assembling,” clustering, and altering its 3D structure to activate itself and carry out its task.
In the past ten years, researchers have created medications to inhibit tankyrase in an effort to treat bowel cancer, but because Wnt signaling is involved in so many different processes, the drugs’ adverse effects prevented them from being tested in clinical settings.
Scientists at the ICR set out to uncover new structural information using cutting-edge cryo-electron microscopy in order to truly comprehend how tankyrase inhibitors function and how to design less harmful treatments. With the use of this incredibly potent type of microscopy, samples are frozen at -180 °C so that minuscule details of protein shape may be observed.
The method allowed them to understand why the formation of fibers is necessary for tankyrase to activate itself, as well as how tankyrase “self-assembles” into these chain-like structures.
Future cancer medications could target the “domains”—specific protein regions associated with various functions—that enable tankyrase to assemble and disassemble into various structures. They also think that different tankyrase inhibitors will have different effects on Wnt signaling depending on the structural domains that the drugs bind to.
It is hoped that scientists will be able to create safer, more potent tankyrase inhibitors, which are urgently required for treating bowel cancer and other conditions to which tankyrase has been linked.
Professor Sebastian Guettler, Deputy Head of the Division of Structural Biology at the Institute of Cancer Research in London and study leader, stated:
“Our study has contributed crucial new knowledge about a specific protein molecule known as tankyrase, which is crucial in bowel cancer and other diseases but which we have not yet fully understood.” We have a lot of drugs to prevent the production of tankyrase, but we lack the fundamental knowledge to use them as treatments.
We’ve demonstrated how tankyrase can be activated and transformed from a “lazy” enzyme to an active one. Future bowel cancer treatments may be possible if we can develop more effective, less harmful drugs to manage this process.
