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A molecular Machine at Work:

Hsp90 protects against Stress

The so-called heat shock protein Hsp90 in its open and its closed (background) form

22.02.2009, Press releases

If cells are stressed, the protein Hsp90 makes an important contribution to their survival. Two groups from the Technische Universität München (TUM) have now clarified how this protein works. The results have been published in two articles of the current online edition of the science magazine Nature Structural and Molecular Biology.

Proteins are the machines of the cell. They fulfill a wide variety of tasks, such as the transport of molecules, the movement of muscles, the chemical conversion of substances and even the folding of other proteins. The so-called heat shock protein Hsp90 is of crucial importance for our cells as it supports many basic processes. It plays a decisive role, for example, in the folding of simple amino acid chains to functioning proteins with a precisely defined spatial structure. Particularly when the cell is highly stressed by heat, poisons or lack of oxygen, production of the protein is increased to limit the damage.

Hsp90 obtains the energy it needs to function by the slow splitting of ATP. This changes the shape of the protein. As with a macroscopic motor, the individual parts move against each other, however by only a few nanometers. Two groups from the TUM, from the Chemistry (Prof. Buchner) and Physics (Prof. Hugel) Departments, have been able to follow this scissor-like movement in real time for the first time and have clarified the individual steps of the reaction mechanism.

In order to be able to track these changes on the nanometer scale, two fluorescent dye molecules were attached at exactly defined positions in the protein and used as a molecular ruler: If one dye is illuminated, the other will more strongly light up the closer it is to the first one. With the aid of this technology (FRET) it has been possible to analyze the motion of individual Hsp90 molecules.

Important and unexpected results include that the process advances in a series of well-defined sub-steps, and also that only part of the energy is converted into mechanical work, i.e. motion. Interestingly, the coupling between “fuel consumption” and motion in the protein can be accelerated or decelerated by additional helper proteins.

These results are not only important for the fundamental understanding of molecular motors, but also for pharmaceutical research, as Hsp90 is an interesting target protein for cancer therapy. If it were possible to switch off the motor in a controlled way, it would be possible to stop the division of cancer cells.

“These two publications nicely show how important interdisciplinary collaboration has become, and how well it works on our campus,” says Buchner. “Here, the two TUM Departments Physics and Chemistry, the two Clusters of Excellence CIPSM and NIM, and also the Central Institute of Medical Engineering (IMETUM) have cooperated very closely. Such results cannot be achieved by an individual working group on its own.”

The work has been supported by Deutsche Forschungsgemeinschaft (SFB 594), Fonds der Chemischen Industrie and Nanoinitiative München (NIM) as well as Munich Center for Integrated Protein Science (CIPSM).

Original publications:

Martin Hessling, Klaus Richter, Johannes Buchner
Dissection of the ATP-induced conformational cycle of the molecular chaperone Hsp90
Nature Structural & Molecular Biology, 16, 287 - 293 (2009)
http://dx.doi.org/10.1038/nsmb.1565

Moritz Mickler, Martin Hessling, Christoph Ratzke, Johannes Buchner, Thorsten Hugel
The large conformational changes of Hsp90 are only weakly coupled to ATP hydrolysis
Nature Structural & Molecular Biology, 16, 281 - 286 (2009),
http://dx.doi.org/10.1038/nsmb.1557

Image:

http://mediatum2.ub.tum.de/node?id=683843

Links:

Protein-folding by chaperones (like Hsp90) (© MPI for Biochemistry; Film needs Quicktime)
Homepage Prof. Buchner
Homepage Prof. Hugel

Contact:

Prof. Dr. Johannes Buchner
Technische Universitaet Muenchen
Department of Chemistry
Lichtenbergstr. 4
D 85747 Garching, Germany
Tel.: +49 89 289 13341
Fax: +49 89 289 13345
E-Mail

Prof. Dr. Thorsten Hugel
Technische Universitaet Muenchen
Department of Physics
James Franck Str. 1
D 85748 Garching, Germany
Tel.: +49 89 289-16781
E-Mail

Kontakt: presse@tum.de

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