Navigation Links
Toronto researchers obtain detailed molecular 'signature' for Tankyrase
Date:12/8/2011

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.


'/>"/>
Contact: Karin Fleming
fleming@lunenfeld.ca
416-586-4800 x2046
Samuel Lunenfeld Research Institute
Source:Eurekalert

Related medicine news :

1. Toronto-based genomics center gets $5 million injection
2. Toronto researchers find first physical evidence bilingualism delays onset of Alzheimers symptoms
3. Toronto XVIV0 Lung Perfusion System allows high-risk lungs to be safely transplanted
4. Toronto Western Hospital study demonstrates improved wait times for patients suffering back pain
5. Toronto homeless report barriers to health care
6. Toronto Marriage Counselling: Stephen Giles, MSW Creates 10-Point Marriage Counselling Needs Test
7. University of Toronto scholars receive prestigious New Directions Fellowships
8. Learn to Dance in a Day -- Beginner Workshop Launches Modern Jive in Toronto
9. Danish mushroom inspires cancer researchers
10. Bone Drugs May Also Battle Breast Cancer, Researchers Say
11. Researchers discover that changes in bioelectric signals cause tadpoles to grow eyes in back, tail
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:5/26/2017)... Massachsetts (PRWEB) , ... May 26, 2017 , ... ... will gather at Boston CEO 2017 on May 30th and 31st at The ... networking forum for leading executives in the life sciences, offering exclusive access to ...
(Date:5/26/2017)... ... May 26, 2017 , ... A new analysis of community health data reveals ... located in the Midwest. With the average cost of healthcare rising and the U.S. ... both the quality and affordability of where they live. An annual 2017 report looked ...
(Date:5/26/2017)... (PRWEB) , ... May 26, 2017 , ... After raising ... Antzy Top gadget will continue to be available at a discounted crowdfunding price on ... with stress wherever they are, I also wanted to bring a fidget toy to ...
(Date:5/26/2017)... ... 26, 2017 , ... Dr. Alex Rabinovich, a highly-skilled oral surgeon specializing in ... post on insurance options. If a Bay Area patient has to search for a ... money. Visiting an in-network provider for a second opinion can ensure a patient receives ...
(Date:5/26/2017)... ... ... Happened in the Garden of Eden”: retells the stories of three Bible figures in modern ... author, Penelope Colt, mother, trader, horse farmer, artist and a former GM journeyman. Born ... At six, they moved to Dayton, Ohio, where Penny graduated high school. At sixteen, ...
Breaking Medicine News(10 mins):
(Date:5/6/2017)... N.Y. , May 5, 2017  Hill-Rom Holdings, ... will add approximately 100,000 square feet to its Welch ... September 2016 its commitment to bring more than 100 ... , where Welch Allyn has maintained a significant presence ... help accommodate these new positions, a large portion of ...
(Date:5/4/2017)... CAESAREA, Israel , May 4, 2017  DarioHealth ... with mobile health and big data solutions, today announced ... an A&D Company, and STI Technologies Limited to lower ... effective immediately. Through STI,s innoviCares card, which is available ... , DarioHealth customers will be eligible for additional ...
(Date:5/3/2017)... 3, 2017  Getinge, a leading global provider ... enhancement and cost efficiency within healthcare and life ... contemporary practice demonstrating that intra-aortic balloon counterpulsation (IABC) ... ill patients. The single-center, retrospective, observational study showed ... MEGA ® 50cc intra-aortic balloon (IAB) in ...
Breaking Medicine Technology: