ncerogenesis.

Apart from neurofibromin, there are other GTPase activating proteins specific for Ras; in living organisms, it is indeed common that identical processes are carried out by different components. The first GAP to be discovered was the p120GAP (Trahey & McCormick, 1987, Science 238, 542-545). In fundamental studies involving biochemical and structural methods, the research team has previously included p120GAP to elucidate the molecular mechanism behind the GTPase activation process. p120GAP, represented by the segment of the protein that is sufficient to stimulate Ras-mediated GTP hydrolysis, complements the active site which is where the reaction takes place. It does so by two strategies: Firstly, it supplies an amino acid (an arginine) that participates directly in the reaction; its mutation to another amino acid destroys GAP activity. Secondly, it stabilizes the functionally most important amino acids on Ras, thereby aligning the catalytic machinery (Scheffzek et al., Science 277, 333-338).

The structure of neurofibromin GAP resembles the structure of the corresponding segment of p120GAP: it is an elongated molecule that is composed of a small and a large domain, the latter of which contains all the functionally important residues. Together with the biochemical analyses, the structural similarity confirms that it functions by the same mechanism. On the basis of the structural work on neurofibromin and p120GAP complexed with Ras, the effect of mutations in the GAP segment, as found in NF1-patients, can be analyzed; e.g. the catalytic arginine contributed by GAP has been found mutated in an NF1 patient; the resulting GAP protein has an intact structure but is completely inactive (Klose et al., 1998, Hum. Mol. Genet. 7,
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Contact: Klaus Scheffzek
Klaus.Scheffzek@mpi-dortmund.mpg.de
Fax: 49-231-1206-23
Max-Planck-Gesellschaft
14-Aug-1998


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