Tankyrase is an important protein that regulates a wide range of processes relevant to cancer and other conditions, such as diabetes, neurodegeneration and fibrosis. It supports 'Wnt signalling', essential for cell division and development and maintaining stem cells. Tankyrase also controls other cell functions critical to cancer, including the maintenance of telomeres at the end of chromosomes. Therefore, tankyrase has received substantial attention as a potential drug target.
Tankyrase is part of the 'PARP family' of proteins, and drugs blocking PARP1 are already in clinical use. However, tankyrase remains poorly understood, with scientists unsure of how the protein is switched on, how it functions and how to block it without causing unwanted side effects.
Tankyrase self-assembles to form filamentous polymers, but how polymerisation contributes to tankyrase function and catalytic activity was unknown.
Scientists at The Institute of Cancer Research in London used cryo-Electron Microscopy (cryo-EM) at eBIC to investigate the architecture of tankyrase filaments. In particular, they were keen to identify any potential contacts made by the catalytic domains, as these interactions may control the effect of polymerisation on tankyrase's activity.
Using helical reconstruction, they revealed the architecture of a tankyrase filament containing the polymerisation and catalytic domains. Surprisingly, the filament turned out to be a double helix, something they didn't anticipate based on previous X-ray crystallography studies. Their results revealed extensive interactions between different domains of tankyrase, including those involving the catalytic domain. Based on subsequent biophysical, biochemical and cell-based studies, the researchers proposed that a polymerisation-induced allosteric switch regulates tankyrase's catalytic functions.
The scientists draw parallels between the activation mechanism of PARP1 and tankyrase for the first time. Similarly to PARP1, they suggest tankyrase works by being recruited to a specific site and 'self-assembling', activating itself by clustering and changing its 3D structure.
Although previous research has developed drugs that block tankyrase - in the hope of treating bowel cancer - they caused too many side effects to reach clinical trials. That's due to Wnt signalling being involved in such a wide range of processes. This work provides novel insights into fundamental biological mechanisms but should also enable the development of novel tankyrase inhibitors and overcome the limitations of currently available molecules.
Pillay, N. et al. Structural basis of tankyrase activation by polymerisation. Nature 612, 162–169 (2022). DOI: 10.1038/s41586-022-05449-8
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