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Study explains molecular basis for cherubism disease

May 15, 2017

Using x-ray crystallography, the team determined the structures of the portion of Tankyrase responsible for substrate binding, bound to a range of different substrates including 3BP2. Using a technique known as fluorescence polarization the researchers then determined the essential signature of the Tankyrase binding motif by which Tankyrase identifies its substrates.

With Dr. Evangelia Petsalaki from Dr. Tony Pawson's laboratory, the researchers scanned the entire inventory of human proteins, searching for the signature sequence that is recognized by Tankyrase, correctly predicting many possible new substrates for the enzyme. The result: a deeper understanding of the biology behind Tankyrase's cellular activities.

"Our work provides answers to two big questions. Firstly, we obtained a visual snapshot of how Tankyrase recognizes its substrates and how mutations characteristic of cherubism lead to illness," said Dr. Guettler, a post-doctoral Fellow in Dr. Sicheri's and Dr. Pawson's labs and first author of the study. "Secondly, we learned more about the possible cellular tasks performed by Tankyrase. The apparent abundance of potential Tankyrase targets and the variety of cellular functions they perform suggests that the complexity of Tankyrase's biological functions has been underappreciated to date."

Inhibitors of PARPs, and among them Tankyrase, have gained considerable attention recently as potential new anti-cancer agents. Inhibition of Tankyrase function may hold promise for treating certain breast cancers as well as other cancers, and therefore the present study may help refine treatment strategies for blocking Tankyrase.

Source: Samuel Lunenfeld Research Institute