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Researchers hone in on mechanism of cell growth protein Ras [Print to PDF] [Print to RTF]

The Ras protein occurs in virtually all living things and is important to all living cells. It is responsible for a lot, but perhaps most importantly it regulates the growth of cells. The molecular mechanism by which the Ras protein accelerates the division of the guanosine tr...
Researchers hone in on mechanism of cell growth protein Ras
The Ras protein occurs in virtually all living things and is important to all living cells. It is responsible for a lot, but perhaps most importantly it regulates the growth of cells. The molecular mechanism by which the Ras protein accelerates the division of the guanosine triphosphate (GTP) molecule, thereby slowing cell growth, has now been described by Prof. Dr Klaus Gerwert, a biophysicist at the Ruhr-Universität Bochum, Germany in the Online Early Edition of the journal PNAS.

His findings followed the combined use of infrared spectroscopy and computer simulations. These were able to show that Ras puts a phosphate chain under tension to such an extent that a phosphate group can very easily detach - the brake for cell growth.

Mutated Ras is involved in tumour formation, because this reaction slows down and the brake for cell growth fails. 'Our findings could help to develop small molecules that restore the Ras proteins to the right speed,' says Prof. Gerwert. 'Such molecules would then be interesting for molecular cancer therapy.'

Diseases such as chronic myeloid leukaemia (CLM) can currently be treated through molecular cancer therapy through drugs like Gleevec; however, molecules with a similar effect against the mutated Ras protein have not yet been found. 'Since we are now able to investigate the reactions of the Ras protein with significantly better resolution, new hope is forming that it will be possible to defuse the mutated molecule using drugs such as Gleevec and restore the rhythm of the cell,' says Prof. Gerwert.

Typically, the Ras protein switches the cell growth off by detaching a phosphate group from the small bound GTP. GTP has three interlinked phosphate groups. If it is present in water, the third phosphate group can split off spontaneously, even without the help of the protein Ras. The process is however very slow. Ras accelerates the splitting by a magnitude of five, and a second protein, called GAP, by a further magnitude of five. What causes this acceleration has now been found by the Ruhr-Universität Bochum team.

What Ras does is bring the chain of three phosphate groups at the GTP into a certain shape. It turns the third and second phosphate group to each other so that the chain is tensioned. 'Like winding up a spring in a toy car by turning a screw,' explains Prof. Gerwert.

'Ras is the screw, the phosphate groups form the spring.' The protein GAP tensions the spring further by also turning the first phosphate group against the second. In this way, the GTP gets into such a high-energy state that the third phosphate group can easily detach from the chain - similar to when a toy car drives off spontaneously after the spring has been wound up.

The results were obtained using a time-resolved Fourier transform infrared spectroscopy (FTIR) developed at the Institute of Biophysics. Through the utilisation of this technique, the scientists track reactions and interactions of proteins with high spatial and temporal resolution much more precisely than using a microscope. 'However, the spectroscopy does not deliver such nice pictures as a microscope, but only very complex infrared spectra,' explains PD Dr Carsten Kötting from the research team. 'Like a secret code that has to be deciphered.'

Due to the enormous computational effort, large molecules such as a complete protein cannot currently be reliably described using these so-called quantum mechanical simulations. Therefore, the researchers limited their analysis to GTP and the part of the Ras or GAP protein that interacts directly with GTP. They described the rest of the proteins with a less elaborate molecular dynamics simulation.

'When bringing together all the different simulations, it is easy to be led astray,' says Till Rudack. 'Therefore you have to check the quality of the results by comparing the simulated with the measured infrared spectra.' If the spectra obtained with both techniques match, the structure of proteins can be determined to an accuracy of a millionth of a micrometre, as was shown in the Ruhr-Universität Bochum study.
Source: Ruhr-Universität Bochum; PNAS

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Record Number: 35047 / Last updated on: 2012-09-21
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