Structure and Activation of GEFs

The structure of the mSos protein (m=mammalian) is shown in Fig. 9.8. Sequence comparison with known Ras-specific GEFs has identified a common domain of ca.200 amino acids, to which nucleotide exchange activity has been assigned. Within this domain, three highly conserved sequence elements can be differentiated, separated by more variable sections. Other structural elements include a PH domain and a Pro-rich binding domain. The Pro-rich sequence fimctions as an attachment site for the SH3 group of Grb2 protein. 

The complex of Grb2 and mSos proteins forms a link between Ras protein and activated receptor tyrosine kinases. The Grb2 protein has two SH2 domains (see 8.5) and a SH3 domain. 

The Sos-Grb2 complex can participate in Ras signal transduction by two pathways. In one pathway, the SH2 domain of Grb2 binds to the phosphotyrosine of the activated receptor, whereby the Grb2-mSos complex, which is predominantly localized in the cytoplasm, is brought to the receptor and thus to the cell membrane (Fig. 9.9). 

In the other pathway, an additional adaptor protein, the She protein (see 8.5), is involved in the signal transduction. The She protein has a phosphotyrosine binding domain (PTB domain) and specifically binds via this domain to autophosphorylated receptors such as the PDGF receptor and the EGF receptor. The She protein is phos-phorylated itself in the process. The phosphotyrosine residues may also serve as attachment points for the SH2 domain of Grb2 protein, whereby the Grb2-Sos complex is attached to the membrane. 

In the membrane-localized form, Sos protein interacts with Ras protein, which is also membrane associated, and induces nucleotide exchange in the latter. It is assumed that relocation of the Grb2-Sos complex from the cytosol to the membrane is the decisive step that establishes binding between the activated receptor and Ras protein. The membrane association of both proteins is sufficient for activation of signal transduction and to switch on the Ras protein, according to this assumption. 

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