The specific and appropriate response of cells to external stimuli requires the integration of multiple signaling pathways. Stimulation of cell surface receptors will initiate cellular signals that are governed by post-translational modifications (e.g., phosphorylations), recruitment of protein binding partners to specific subcellular domains, such as the membrane and through protein–protein interactions. One of the major goals of scientists who study signal transduction is to determine the mechanisms that control cross-talk between signaling cascades and to determine how specificity in signaling is achieved. An emerging class of proteins that are major contributors to these processes are adaptor (or adapter) proteins. Adaptor proteins contain a variety of protein-binding modules that link protein-binding partners together and facilitate the creation of larger signaling complexes. By linking specific proteins together, cellular signals can be propagated that elicit an appropriate response from the cell to the environment. Specificity in signaling would be achieved by the type of protein binding modules encoded by the adaptor protein, the sequence of these domains or motifs that would dictate specificity in binding, as well as the subcellular localization and the proximity of binding partners. Thus, adaptor proteins are positioned to regulate cell signaling in a spatial and temporal fashion.
An appreciation for the emergence and recognition of adaptor proteins can be traced back to earlier studies that defined functional domains within proteins and the subsequent identification of their function. Based on studies of glycolytic enzyme pathways, the eminent X-ray crystallographer Michael G Rossman proposed that ‘domains’ within a protein could be defined based on (1) homologous sequences in other proteins, (2) structure, (3) spatial separation within a protein, (4) function and (5) an active center (Rossman, 1981, Phil. Trans. Roy. Soc. Lond., pp. 191–203). Not long afterward, Pawsons and colleagues used computer-based searching techniques to identify the src-homology 2 (SH2) domain within the amino terminus of the Src nonreceptor tyrosine kinase and verified the presence of this domain in other signaling proteins. Biochemical analyses by this group demonstrated the function of the SH2 domain and not long afterward, a number of other protein binding modules were identified, such as the SH3, PH, WW and other domains, as well as the conservative structure of the opposing binding motifs. Deletional mutagenesis studies by Parsons and colleagues as well as others demonstrated that the integrity of these protein-binding modules was functionally required for v-Src or Src527F to transform cells. Here, mutations in the SH2 and SH3 domains of v-Src or Src527F were able to block the ability of these oncogene products to transform cells while having little effect on the high protein tyrosine-specific kinase activity of Src that is associated with transformation-competence. Ultimately, the structural analysis of these modular domains using X-ray crystallography or NMR demonstrated the active centers of these domains and the mechanisms by which they facilitate protein-protein interactions. Collectively, these data demonstrated the structure and function of protein binding domains and underscored the importance of protein-protein interactions in modulating cellular signaling.
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