Toronto researchers obtain detailed molecular 'signature' for Tankyrase

December 08, 2011

Toronto, ON -- The Samuel Lunenfeld Research Institute's Drs. Frank Sicheri, Tony Pawson and Sebastian Guettler, in collaboration with Dr. Robert Rottapel at the Ontario Cancer Institute, have uncovered the detailed architecture of a crucial component of Tankyrase, a protein linked to the bone development disorder cherubism and involved in a myriad of cellular processes. The discovery is the first structural insight into precisely how the enzyme correctly identifies its targets, or substrates. The work provides researchers with a greater understanding of Tankyrase's cellular control processes, and may also lead to the development of new designer drugs to treat cancer.

"Until now, we did not understand, from a structural perspective, how Tankyrase identifies its substrates," said Dr. Sicheri, Lunenfeld Senior Investigator and one of the lead authors of the study. "At atomic resolution, we now have a clearer picture of what these substrates may be, and have new insight into possible novel functions of Tankyrase."

The findings are available online today and will be published in the December 9 issue of the leading biomedical journal Cell.

Tankyrase is a poly(ADP-ribose)polymerase (PARP) -- one protein of a family of enzymes that modify other proteins with chains of ADP-ribose and affect many cellular processes. The modification reactions carried out by Tankyrase can directly alter some proteins' functions, bring proteins together in protein complexes, or can mark others for degradation.

Initially intrigued by Tankyrase because of its involvement in cherubism (a rare genetic disorder caused by mutations in the signaling protein 3BP2), the researchers built upon the findings of Dr. Rottapel's laboratory. This laboratory found that Tankyrase normally recognizes 3BP2 and targets it for destruction. The amino acids mutated in cherubism coincide with precisely the region in 3BP2 that is recognized by Tankyrase, or the "Tankyrase binding motif." Cherubism mutations in 3BP2 prevent binding of Tankyrase and therefore result in the accumulation of 3BP2 protein in the cell. Dr. Rottapel's findings also appear in the same issue of Cell.

The goal of Dr. Sicheri and his team's work was to uncover the exact mechanism by which Tankyrase recruits its substrates, to explain why cherubism mutations in 3BP2 disrupt Tankyrase binding and thereby learn more about how the enzyme works.

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.
-end-
The study was supported by the Canadian Institutes of Health Research.

Samuel Lunenfeld Research Institute

Related Protein Articles from Brightsurf:

The protein dress of a neuron
New method marks proteins and reveals the receptors in which neurons are dressed

Memory protein
When UC Santa Barbara materials scientist Omar Saleh and graduate student Ian Morgan sought to understand the mechanical behaviors of disordered proteins in the lab, they expected that after being stretched, one particular model protein would snap back instantaneously, like a rubber band.

Diets high in protein, particularly plant protein, linked to lower risk of death
Diets high in protein, particularly plant protein, are associated with a lower risk of death from any cause, finds an analysis of the latest evidence published by The BMJ today.

A new understanding of protein movement
A team of UD engineers has uncovered the role of surface diffusion in protein transport, which could aid biopharmaceutical processing.

A new biotinylation enzyme for analyzing protein-protein interactions
Proteins play roles by interacting with various other proteins. Therefore, interaction analysis is an indispensable technique for studying the function of proteins.

Substituting the next-best protein
Children born with Duchenne muscular dystrophy have a mutation in the X-chromosome gene that would normally code for dystrophin, a protein that provides structural integrity to skeletal muscles.

A direct protein-to-protein binding couples cell survival to cell proliferation
The regulators of apoptosis watch over cell replication and the decision to enter the cell cycle.

A protein that controls inflammation
A study by the research team of Prof. Geert van Loo (VIB-UGent Center for Inflammation Research) has unraveled a critical molecular mechanism behind autoimmune and inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis.

Resurrecting ancient protein partners reveals origin of protein regulation
After reconstructing the ancient forms of two cellular proteins, scientists discovered the earliest known instance of a complex form of protein regulation.

Sensing protein wellbeing
The folding state of the proteins in live cells often reflect the cell's general health.

Read More: Protein News and Protein Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.