Two hydrophobic residues can determine the specificity of mitogen-activated protein kinase docking interactions.
A Jane BardwellLee BardwellPublished in: The Journal of biological chemistry (2015)
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 1 or 2 key hydrophobic residues in this submotif is sufficient to turn a weak JNK-binding D-site into a strong one, or vice 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 versus JNK, as predicted. These results provide new insights into docking specificity and suggest that this specificity can evolve rapidly by changes to just 1 or 2 amino acids.
Keyphrases
- signaling pathway
- transcription factor
- molecular dynamics
- molecular dynamics simulations
- protein protein
- induced apoptosis
- cell death
- pi k akt
- ionic liquid
- structural basis
- dna binding
- aqueous solution
- amino acid
- cell proliferation
- oxidative stress
- tyrosine kinase
- heat shock
- human immunodeficiency virus
- hepatitis c virus
- antiretroviral therapy
- heat shock protein
- heat stress