In order for activated RTKs and cytokine receptors to activate Ras, two cytosolic proteins—GRB2 and Sos—must first be recruited to provide a link between the receptor and Ras (Figure 16-21). GRB2 is an adapter protein, meaning that it has no enzyme activity and serves as a link, or scaffold, between two other proteins—in this case, between the activated receptor and Sos. Sos is a guanine nucleotide exchange protein (GEF) that catalyzes conversion of inactive GDP-bound Ras to the active GTP-bound form.

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GRB2 is able to serve as an adapter protein because of its SH2 domain, which binds to a specific phosphotyrosine residue in the cytosolic domain of an activated RTK (or cytokine receptor). In addition to its SH2 domain, the GRB2 adapter protein contains two SH3 domains, which bind to Sos (see Figure 16-21). Like phosphotyrosine-binding SH2 domains, SH3 domains are present in a large number of proteins involved in intracellular signaling. Although the three-dimensional structures of various SH3 domains are similar, their specific amino acid sequences differ. The SH3 domains in GRB2 selectively bind to proline-rich sequences in Sos; different SH3 domains in other proteins bind to proline-rich sequences distinct from those in Sos.

Proline residues play two roles in the interaction between an SH3 domain in an adapter protein (e.g., GRB2) and a proline-rich sequence in another protein (e.g., Sos). First, the proline-rich sequence assumes an extended conformation that permits extensive contacts with the SH3 domain, thereby facilitating interaction. Second, a subset of the prolines fit into binding “pockets” on the surface of the SH3 domain (Figure 16-22). Several nonproline residues also interact with the SH3 domain and are responsible for determining the binding specificity. Hence the binding of proteins to SH3 and to SH2 domains follows a similar strategy: certain residues provide the key structural motif necessary for binding, and neighboring residues confer specificity to the binding.