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J Biol Chem. 2015 Oct 30;290(44):26661-74. doi: 10.1074/jbc.M115.691436. Epub 2015 Sep 14.

Two hydrophobic residues can determine the specificity of mitogen-activated protein kinase docking interactions.

Author information

  • 1From the Department of Developmental and Cell Biology, Center for Complex Biological Systems, University of California, Irvine, California 92697.
  • 2From the Department of Developmental and Cell Biology, Center for Complex Biological Systems, University of California, Irvine, California 92697 bardwell@uci.edu.

Abstract

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.

KEYWORDS:

c-Jun N-terminal kinase (JNK); cell signaling; docking site; dual-specificity kinase; mitogen-activated protein kinase (MAPK); phosphorylation; protein complex; protein kinase; protein phosphorylation; substrate specificity

PMID:
26370088
PMCID:
PMC4646321
DOI:
10.1074/jbc.M115.691436
[PubMed - indexed for MEDLINE]
Free PMC Article
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