title: Two hydrophobic residues can determine the specificity of mitogen-activated protein kinase docking interactions.
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.
authors.affiliation: From the Department of Developmental and Cell Biology, Center for Complex Biological Systems, University of California, Irvine, California 92697.
authors.forename: A Jane
authors.initials: AJ
authors.lastname: Bardwell
authors.affiliation: From the Department of Developmental and Cell Biology, Center for Complex Biological Systems, University of California, Irvine, California 92697 bardwell@uci.edu.
authors.forename: Lee
authors.identifier: http://orcid.org/0000-0002-2393-8363
authors.initials: L
authors.lastname: Bardwell
mesh_terms: D051698:Activating Transcription Factor 2 / Q000737:chemistry* / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D005786:Gene Expression Regulation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000737:chemistry* / Q000235:genetics; D048670:MAP Kinase Kinase 4 / Q000737:chemistry* / Q000235:genetics; D048669:MAP Kinase Kinase 6 / Q000737:chemistry* / Q000235:genetics; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry* / Q000235:genetics; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D007527:Isoenzymes; D011993:Recombinant Fusion Proteins; D048031:JNK Mitogen-Activated Protein Kinases; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048670:MAP Kinase Kinase 4; D048669:MAP Kinase Kinase 6; C482559:MAP2K4 protein, human; C482566:MAP2K6 protein, human
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