From Protein Interactions to Complex Physiology

Docking or adaptor proteins may provide the building blocks from which complex cellular biological regulatory systems could be built during the course of evolution. Hardy et al . examined the docking protein ShcA, which has a phosphotyrosine binding (PTB) domain and a Src homology 2 (SH2) domain, each of which can bind to phosphorylated receptors and other proteins. Shc proteins also contain tyrosine residues that become phosphorylated and serve as binding sites for the adaptor protein Grb2 (growth factor receptor-bound protein 2). In mice that expressed mutant proteins with one or more domains altered, the PTB domain was essential for development of the heart, but the SH2 domain and Grb2-binding domains were not. However, successful development of skeletal muscle required that the PTB, SH2, and Grb2-binding domains be present within the same Shc molecule. Thus, acquisition of new protein-protein interaction motifs within proteins and their distinct use in various cell types or organisms may support complex physiological functions. W. R. Hardy, L. Li, Z. Wang, J. Sedy, J. Fawcett, E. Frank, J. Kucera, T. Pawson, Combinatorial ShcA docking interactions support diversity in tissue morphogenesis. Science 317 , 251-256 (2007). [Abstract] [Full Text]