title: Substrate discrimination among mitogen-activated protein kinases through distinct docking sequence motifs.
abstract: Mitogen-activated protein kinases (MAPKs) mediate cellular responses to a wide variety of extracellular stimuli. MAPK signal transduction cascades are tightly regulated, and individual MAPKs display exquisite specificity in recognition of their target substrates. All MAPK family members share a common phosphorylation site motif, raising questions as to how substrate specificity is achieved. Here we describe a peptide library screen to identify sequence requirements of the DEF site (docking site for ERK FXF), a docking motif separate from the phosphorylation site. We show that MAPK isoforms recognize DEF sites with unique sequences and identify two key residues on the MAPK that largely dictate sequence specificity. Based on these observations and computational docking studies, we propose a revised model for MAPK interaction with substrates containing DEF sites. Variations in DEF site sequence requirements provide one possible mechanism for encoding complex target specificity among MAPK isoforms.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Sheridan
authors.forename: Yong
authors.initials: Y
authors.lastname: Kong
authors.forename: Sirlester A
authors.initials: SA
authors.lastname: Parker
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Dalby
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Turk
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D051381:Rats; D012984:Software; D013379:Substrate Specificity / Q000502:physiology
chemical_list: D007527:Isoenzymes; D048049:Extracellular Signal-Regulated MAP Kinases