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Abstract:
Mitogen-activated protein kinases (MAPKs) have a docking groove that interacts
with linear "docking" motifs in binding partners. To determine the structural
basis of binding specificity between MAPKs and docking motifs, we
quantitatively analyzed the ability of 15 docking motifs from diverse MAPK
partners to bind to c-Jun amino-terminal kinase 1 (JNK1), p38α, and
extracellular signal�regulated kinase 2 (ERK2). Classical docking motifs
mediated highly specific binding only to JNK1, and only those motifs with a
sequence pattern distinct from the classical MAPK binding docking motif
consensus differentiated between the topographically similar docking grooves of
ERK and p38α. Crystal structures of four complexes of MAPKs with docking
peptides, representing JNK-specific, ERK-specific, or ERK- and p38-selective
binding modes, revealed that the regions located between consensus positions in
the docking motifs showed conformational diversity. Although the consensus
positions in the docking motifs served as anchor points that bound to common
MAPK surface features and mostly contributed to docking in a nondiscriminatory
fashion, the conformation of the intervening region between the anchor points
mostly determined specificity. We designed peptides with tailored MAPK binding
profiles by rationally changing the length and amino acid composition of
intervening regions located between anchor points. These results suggest a
coherent structural model for MAPK docking specificity that reveals how short
linear motifs binding to a common kinase docking groove can mediate diverse
interaction patterns and contribute to correct MAPK partner selection in
signaling networks.
