Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Structure Determined for p53 Tumor Suppressor Protein

19.07.2006
More than half of human cancers involve mutations in the p53 tumor-suppressor gene, suggesting the critical role played by the normal p53 protein in defending against cancer. Similarly, roughly 95 percent of cancer-causing mutations in the p53 protein occur in its DNA-binding core domain, pointing to this region of the p53 protein as being pivotal to its anti-cancer activity.

Clearly, a detailed view of the p53 protein in direct contact with DNA could provide important insights into preventing and treating an array of human cancers. To date, however, despite having learned a good deal about the protein’s biochemistry over the years, scientists have been unable to “see” the protein – using the tools of structural biology – bound to DNA in its naturally occurring form. This naturally occurring form contains a pairing of two p53 proteins, called a dimer, that then binds to a second p53 dimer in a similar way to create the precisely oriented four-protein complex, called a tetramer, that binds DNA.

Now, in a new study featured as a “paper of the week” and on the cover of the July 21 issue of the Journal of Biological Chemistry, researchers at The Wistar Institute have successfully determined the three-dimensional structure of the p53 protein bound as a dimer to DNA and used the structure to produce an accurate model of the p53 tetramer bound to DNA.

“The bottom line is that we now have a detailed picture of how p53 binds DNA,” says Ronen Marmorstein, Ph.D., a professor in the Gene Expression and Regulation Program at Wistar and senior author on the study. “Given the fact that p53 is an important tumor suppressor that is mutated in the majority of human cancers, this will undoubtedly be useful information.”

Earlier work had shown how p53 binds to DNA as a stand-alone entity, a form that does not represent the natural state of p53 binding to DNA. The present work captures p53 bound to DNA in its natural dimeric units and thus allows Marmorstein and colleagues to make new and potentially significant insights into p53 function.

One new insight from the current study, for example, is that the point of contact between the two core domains of a pair of p53 proteins forming a dimer tracks to a part of the protein often mutated in cancers. This suggests that the interface between the two proteins of the dimer is likely as important for the proper functioning of the tetramer as its interface with DNA, which also depends on the interface of the core domains of the two p53 proteins that form a dimer.

In seeking to determine the structure of p53 bound to DNA, the challenge for the scientists was that their efforts to crystallize the p53 dimer bound to DNA consistently resulted in structures that could not bind to DNA. (Crystallization is a prerequisite for obtaining the type of three-dimensional image sought in this study.) The researchers found that the dimers formed in solution prior to crystallization attempts took on a form that was incompatible with DNA binding.

“There’s an inactive form of the p53 dimer that’s unable to bind DNA in the correct fashion,” Marmorstein explains. “We knew there had to be a structural rearrangement of the core domains to allow p53 to bind DNA as a dimer. The core domain is what’s binding the DNA, but within the dimer, the two cores have to be in the proper orientation to bind DNA.

“So we decided that we needed to somehow lock the protein into a conformation that’s compatible with the dimer binding to DNA. We used a chemical trick in which we modified a DNA base to allow it to attach directly to a part of the protein’s core domain. That allowed us to trap the form of the p53 dimer that’s compatible with DNA binding. And we solved the structure. We saw what it looked like.”

The lead author on the Journal of Biological Chemistry study is William C. Ho, affiliated with both Wistar and the University of Pennsylvania. Mary X. Fitzgerald, affiliated with Wistar and the University of Pennsylvania School of Medicine, is also a co-author. Marmorstein is the senior author.

Support for the research was provided by the National Institutes of Health and the Department of Defense. Additional support came from the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health. The work also relied on research conducted at the Cornell High Energy Synchrotron Source, which is supported by the National Science Foundation.

The Wistar Institute is an international leader in biomedical research, with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. Discoveries at Wistar have led to the creation of the rubella vaccine that eradicated the disease in the U.S., rabies vaccines used worldwide, and a new rotavirus vaccine approved in 2006. Wistar scientists have also identified many cancer genes and developed monoclonal antibodies and other important research tools. Today, Wistar is home to eminent melanoma researchers and pioneering scientists working on experimental vaccines against flu, HIV, and other diseases. The Institute works actively to transfer its inventions to the commercial sector to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today’s Discoveries – Tomorrow’s Cures.

Franklin Hoke | EurekAlert!
Further information:
http://www.wistar.org

More articles from Life Sciences:

nachricht Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz

nachricht Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Fighting drug resistant tuberculosis – InfectoGnostics meets MYCO-NET² partners in Peru

28.04.2017 | Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

 
Latest News

Wireless power can drive tiny electronic devices in the GI tract

28.04.2017 | Medical Engineering

Ice cave in Transylvania yields window into region's past

28.04.2017 | Earth Sciences

Nose2Brain – Better Therapy for Multiple Sclerosis

28.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>