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A chaperone for the 'guardian of the genome'
Date:9/7/2011

nced Study at the TU Muenchen (TUM-IAS) since October 2008.

Using nuclear magnetic resonance (NMR) spectroscopy, the scientists at the Bavarian NMR Center in Garching were able for the first time to characterize the interaction surfaces between Hsp90 and p53 and show that p53 binds to Hsp90 in an already structured form. p53 is thus kept in a functional state until this interaction is terminated by its actual intended binding partner, DNA. To keep p53 in the desired state, a number of interaction surfaces at different sites of the Hsp90 protein must interact in a closely coordinated manner.

In nuclear magnetic resonance spectroscopy, a sample of dissolved proteins is placed in an extremely strong, homogenous magnetic field and exposed to a complex sequence of radio frequency impulses. The atomic nuclei of the protein react to these impulses with a characteristic response frequency that depends on the environment of the respective nucleus. The scientists can measure this response. "Every single stimulated nucleus responds at its own frequency," explains Kessler. "In this way we can determine the connections between individual nuclei and thus deduce the structure of the protein." When p53 binds to Hsp90, the response frequencies at specific sites of the protein change. Based on these changes, the scientists can infer the sites at which p53 binds to Hsp90.

The new insight on the interaction surfaces between Hsp90 and p53 are of great significance in the development of new cancer medications. After all, Hsp90 stabilizes not only intact p53, but also, and above all, mutated versions of the protein. This leads to a negative effect of the chaperone. The reason: The defective p53 sustained by Hsp90 binds, in its turn, to an active p53 and inactivates it potentially leading to a tumor. In the future, medication that acts on the discovered sites could prevent Hsp90 from attaching to and stabilizing defective p53 in cancer cells. "Many of the alter
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Contact: Dr. Markus Bernards
bernards@zv.tum.de
0049-892-892-2562
Technische Universitaet Muenchen
Source:Eurekalert

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