Two Hydrophobic Residues Can Determine The Specificity Of MAP Kinase Docking Interactions [Cell Biology]

September 14th, 2015 by Bardwell, A. J., Bardwell, L.

Mitogen-activated protein kinases (MAPKs) bind to many of their upstream regulators and downstream substrates via a short docking motif (the D-site) on their binding partner. MAPKs that are in different families (e.g. ERK, JNK and p38) can bind selectively to D-sites in their authentic substrates and regulators, while discriminating against D-sites in other pathways. Here we demonstrate that the short hydrophobic region at the distal end of the D-site plays a critical role in determining the high selectivity of JNK MAPKs for docking sites in their cognate MAPK kinases. Changing just one or two key hydrophobic residues in this submotif is sufficient to turn a weak JNK-binding D-site into a strong one, or visa versa. These specificity-determining differences are also found in the D-sites of the ETS-family transcription factors Elk-1 and Net. Moreover, swapping two hydrophobic residues between these D-sites switches the relative efficiency of Elk-1 and Net as substrates for ERK vs. JNK as predicted. These results provide new insights into docking specificity, and suggest that this specificity can evolve rapidly by changes to just one or two amino acids.