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 A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>