Structural basis of p38α regulation by hematopoietic tyrosine phosphatase

Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island, USA.
Nature Chemical Biology (Impact Factor: 13). 11/2011; 7(12):916-924. DOI: 10.1038/nchembio.707
Source: PubMed


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.

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Available from: Bartosz Różycki, Oct 02, 2015
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    • "This is of special interest, as recent studies have shown that while KIM-peptides derived from KIM-containing regulatory proteins and substrates readily discriminate between ERK2/p38 and JNK, they discriminate poorly between ERK2 and p38 [7]. We recently reported detailed ITC, NMR as well as small angle X-ray scattering (SAXS) data of the interactions between the MAPK p38α and the KIM-PTP family members [14], [15]. Furthermore, we also compared the interaction the immune-specific KIM-PTP, HePTP, with p38α and ERK2 [16], [17]. "
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