Scientists have revealed the inner workings of a key protein involved in a wide range of cellular processes – paving the way for better and less toxic cancer drugs.
Using Nobel Prize-winning microscopy techniques, researchers have revealed how the tanquerase protein is turned on and off by self-assembly into three-dimensional chain-like structures.
Their study was published in the journal naturereveals important structural insights into the elusive but important protein tanquerase, which plays a particularly important role in helping to drive bowel cancer.
Scientists at the Institute of Cancer Research, London, believe their research will open the door to new types of cancer treatment that can control Tanquerazi more precisely than is currently possible, with fewer side effects.
The fundamental discovery could have implications for the treatment of various types of cancer, as well as diabetes and inflammatory, cardiac and neurodegenerative diseases.
The study was funded mainly by Cancer Research UK, Wellcome, and the Institute for Cancer Research (ICR), which is itself a charity and research institute.
Tankyrase is an important protein that supports “Wnt signaling”—signals that are essential for the body to maintain stem cells and carry out processes such as cell division and development, but that, when uncontrolled, can fuel bowel cancer, among other things. Tankyrase also controls other cell functions important for cancer, such as maintenance of the ends of chromosomes, telomeres.
In contrast to the PARP1 protein of the same ‘PARP family’, tankyrase is still not well understood. While drugs that block PARP1 have already reached the clinic, scientists still don’t fully understand how tankyrase is turned on, how it works or how to block it without causing unwanted side effects.
In this study, scientists have drawn parallels between the activation mechanism of PARP1 and tankyrase for the first time. They suggest that, similar to PARP1, tankyrase acts by being recruited to a specific site and ‘self-assembling’, assembling and altering its three-dimensional structure to activate itself and perform its function.
In the past decade, scientists have developed tanquerase-blocking drugs in an effort to treat bowel cancer — but because Wnt signaling is involved in a wide range of processes, the drugs had too many side effects for them to get to clinical trials.
To understand how Tankyrase inhibitors work and how to develop less toxic treatments, scientists at ICR set out to discover new structural information using state-of-the-art cryoelectron microscopy. This extremely powerful type of microscopy freezes samples at -180 °C to enable imaging of fine details of protein shape.
This approach allowed them to visualize and capture how the tanks ‘self-assemble’ into fibres–chain-like structures–and why the formation of fibrils is necessary for Tanqueriz to activate itself.
The researchers believe that ‘domains’ – specific regions of a protein associated with various functions – that allow cGMP to assemble and disassemble into different structures are exciting targets for future cancer drugs. They also believe that, depending on which structural domains the drugs bind to, not all tanquerase inhibitors will affect Wnt signaling in the same way.
The hope is that researchers can design structurally different inhibitors of tanquerase—safer and more effective inhibitors that are urgently needed to treat bowel cancer and other diseases to which tanquerase has been linked.
Study leader Professor Sebastian Gitler, Deputy Head of Structural Biology at The Institute of Cancer Research, London, said:
“Our study provided new vital information about a specific protein molecule called tankyrase, which plays an important role in bowel cancer and other diseases but has so far eluded our understanding. We’re chasing — we have all these drugs to prevent tankyrase from being created, but we don’t have enough basic understanding of their use.” as a treat.
“We have shown how tankyrase is turned on and can go from a ‘lazy’ enzyme to an active enzyme. If we can produce better, less toxic drugs to control this process, we could pave the way for effective bowel cancer treatment in the future.”