Researchers at the Wistar Institute successfully determined, and reported in the July 21 issue of the Journal of Biological Chemistry, 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 in cells.
According to the Wistar Institute, 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.
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. The researchers say the present work captures p53 bound to DNA in its natural dimeric units and thus allows new and potentially significant insights into p53 function.
“There’s an inactive form of the p53 dimer that is unable to bind DNA in the correct fashion,” Ronen Marmorstein, Ph.D., a professor in the gene expression and regulation program at Wistar and senior author on the study, 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 is 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.”