title: Molecular basis of MAP kinase regulation.
abstract: Mitogen-activated protein kinases (MAPKs; ERK1/2, p38, JNK, and ERK5) have evolved to transduce environmental and developmental signals (growth factors, stress) into adaptive and programmed responses (differentiation, inflammation, apoptosis). Almost 20 years ago, it was discovered that MAPKs contain a docking site in the C-terminal lobe that binds a conserved 13-16 amino acid sequence known as the D- or KIM-motif (kinase interaction motif). Recent crystal structures of MAPK:KIM-peptide complexes are leading to a precise understanding of how KIM sequences contribute to MAPK selectivity. In addition, new crystal and especially NMR studies are revealing how residues outside the canonical KIM motif interact with specific MAPKs and contribute further to MAPK selectivity and signaling pathway fidelity. In this review, we focus on these recent studies, with an emphasis on the use of NMR spectroscopy, isothermal titration calorimetry and small angle X-ray scattering to investigate these processes.
authors.affiliation: Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island, 02912; Department of Chemistry, Brown University, Providence, Rhode Island, 02912.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Peti
authors.forename: Rebecca
authors.initials: R
authors.lastname: Page
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D016384:Consensus Sequence; D005786:Gene Expression Regulation; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000737:chemistry* / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D053838:Scattering, Small Angle; D020539:Sequence Analysis, Protein; D015398:Signal Transduction; D013379:Substrate Specificity; D014961:X-Ray Diffraction
chemical_list: D020929:Mitogen-Activated Protein Kinase Kinases
keywords: D-motif; DUSP; ERK; JNK; KIM; MAP kinase; NMR; PTP; SAXS; kinase interaction motif; p38; structure