Navigation Links
DNA-bound p53 Tumor Suppressor Protein Structure Determined

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 th us 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."

(Source: Newswis)
'"/>




Related medicine news :

1. Use of Cellular Phones associated with Increased risk of Brain Tumors
2. Radiofrequency Energy Cooks Tumors Without Surgery
3. New Liver Tumor Treatment
4. Latest Tumor Classification More Informative
5. New Technique For Benign Breast Tumors
6. Another Treatment Option for Benign Tumors
7. Understanding The Origin Of Tumors
8. Outpatient Treatment Possible For Patients with Uterine Fibroid Tumors
9. Stem Cells, Tumor Cells Share Similar Properties: Scope For Treatment and Prevention?
10. Lipoma Arborescens: A Rare Tumor Of The Knee
11. Researchers Develop Mouse Model Of Brain Tumor
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:5/4/2016)... ... May 04, 2016 , ... The RIDER Institute ... development of DRACO broad-spectrum antiviral therapeutics. DRACOs have proven effective against all 18 ... 3, 2016 at http://igg.me/at/EndTheVirus and runs for 60 days, we are ...
(Date:5/4/2016)... ... ... Nike Rugby Camp's success is due in large part to Ethan Willis ... Camps and current Nike Camp director, has offered an all abilities rugby camp staffed ... for our eighth summer here in San Diego,” says Willis. "We take great pride ...
(Date:5/4/2016)... , ... May 04, 2016 , ... ... master charity program created to assist the people of their local community. The ... nonprofit organizations and community leaders. Their hope is to bring awareness to important ...
(Date:5/4/2016)... ... May 04, 2016 , ... Dr. Elyson and Dr. Assili, dentist ... their office. Wisdom tooth removal, a common dental procedure, is performed for many adolescents ... improperly erupted, resulting in risks of complications. By providing wisdom tooth removal surgery at ...
(Date:5/4/2016)... , ... May 04, 2016 , ... Francesca Loparco, Co-Founder ... her life forever with a same-day LASIK procedure at Christenbury Eye Center. ... Dr. Jonathan Christenbury performed her surgery the same day as her in-office consultation and ...
Breaking Medicine News(10 mins):
(Date:5/4/2016)... 2016 Research and ... Acute lymphocytic Leukemia Market and Competitive Landscape ...      (Logo: http://photos.prnewswire.com/prnh/20160330/349511LOGO ... Market and Competitive Landscape Highlights 2016, provides ... products, Acute Lymphocytic Leukemia epidemiology, Acute Lymphocytic ...
(Date:5/3/2016)... 2016  Axiogenesis has acquired a major investment from Sino-German High-Tech Fund to further expand product development, strengthen its ... http://photos.prnewswire.com/prnh/20160503/362921 ... ... ... ...
(Date:5/3/2016)... ORANGE COUNTY, Calif. , May 3, 2016  While you may be familiar with watching ... 4K resolution , also known as ultra-high-definition or 8MP in the Medical Industry.  Ampronix  is ... class manufacturer of innovative technology. Photo - http://photos.prnewswire.com/prnh/20160502/362730 ... ... ...
Breaking Medicine Technology: