title: Structural basis of p38α regulation by hematopoietic tyrosine phosphatase.
abstract: MAP kinases regulate essential cellular events, including cell growth, differentiation and inflammation. The solution structure of a complete MAPK-MAPK-regulatory protein complex, p38α-HePTP, was determined, enabling a comprehensive investigation of the molecular basis of specificity and fidelity in MAPK regulation. Structure determination was achieved by combining NMR spectroscopy and small-angle X-ray scattering data with a new ensemble calculation-refinement procedure. We identified 25 residues outside of the HePTP kinase interaction motif necessary for p38α recognition. The complex adopts an extended conformation in solution and rarely samples the conformation necessary for kinase deactivation. Complex formation also does not affect the N-terminal lobe, the activation loop of p38α or the catalytic domain of HePTP. Together, these results show how the downstream tyrosine phosphatase HePTP regulates p38α and provide for fundamentally new insights into MAPK regulation and specificity.
authors: Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island, USA.
authors: Dana M
authors: DM
authors: Francis
authors: Bartosz
authors: B
authors: Różycki
authors: Dorothy
authors: D
authors: Koveal
authors: Gerhard
authors: G
authors: Hummer
authors: Rebecca
authors: R
authors: Page
authors: Wolfgang
authors: W
authors: Peti
mesh_terms: D000595:Amino Acid Sequence; D048308:Mitogen-Activated Protein Kinase 14 / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D048308:Mitogen-Activated Protein Kinase 14; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6