Large protein binding regions such as the SH2, SH3, and PH domains are critically important for the proper association and alignment of protein partners and their subsequent transmittal of intracellular signals. In comparison, the specific ligands for these binding domains are quite small, with specificity usually conferred within a span of seven or eight amino acids. Tanoue et al. have uncovered new docking motifs in MAP kinases and their upstream and downstream counterparts. A small cluster of negatively charged residues on the MAPKs ERK1 and ERK2, with the core consensus D-P/T-E/D/S/T-D/E [referred to as the common docking (CD) motif], electrostatically interacted with a cluster of positively charged residues found on their activators, inactivators, and substrates. Coexpression studies revealed that mutation of either charged cluster severely abrogated protein-protein binding, whereas in vitro kinase experiments demonstrated that the docking interactions increased enzymatic activity. Additionally, only one protein at any given time could bind the MAPK CD motif. Thus, it is conceivable that phosphorylation or dephosphorylation of MAPKs and the proteins that associate with them may induce conformation changes that allow one protein to dissociate as another binds to the CD motif. Such a mechanism might contribute to specific hierarchical signal transduction in MAPK pathways.
Tanoue, T., Adachi, M., Moriguchi, T., and Nishida, E. (2000) A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nat. Cell Biol. 2: 110-116. [Online Journal]