Two Hydrophobic Residues Can Determine the Specificity of Mitogen-activated Protein Kinase Docking Interactions

被引:22
作者
Bardwell, A. Jane [1 ]
Bardwell, Lee [1 ]
机构
[1] Univ Calif Irvine, Dept Dev & Cell Biol, Ctr Complex Biol Syst, Irvine, CA 92697 USA
基金
美国国家卫生研究院;
关键词
SIGNAL-REGULATED KINASE; HIGH-AFFINITY BINDING; MAP KINASES; SITES; SUBSTRATE; JNK; MECHANISMS; INHIBITOR; PATHWAYS; MOTIFS;
D O I
10.1074/jbc.M115.691436
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:26661 / 26674
页数:14
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