The differential regulation of p38α by the neuronal kinase interaction motif protein tyrosine phosphatases, a detailed molecular study.
The MAP kinase p38α is essential for neuronal signaling. To better understand the molecular regulation of p38α we used atomistic and molecular techniques to determine the structural basis of p38α regulation by the two neuronal tyrosine phosphatases, PTPSL/PTPBR7 (PTPRR) and STEP (PTPN5). We show that, despite the fact that PTPSL and STEP belong to the same family of regulatory proteins, they interact with p38α differently and their distinct molecular interactions explain their different catalytic activities. Although the interaction of PTPSL with p38α is similar to that of the previously described p38α:HePTP (PTPN7) complex, STEP binds and regulates p38α in an unexpected manner. Using NMR and small-angle X-ray scattering data, we generated a model of the p38α:STEP complex and define molecular differences between its resting and active states. Together, these results provide insights into molecular regulation of p38α by key regulatory proteins.
Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI 02912, USA.
Dana May
DM
Francis
Ganesan Senthil
GS
Kumar
Dorothy
D
Koveal
Antoni
A
Tortajada
Rebecca
R
Page
Wolfgang
W
Peti
D020134:Catalytic Domain; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000737:chemistry*; D054634:Receptor-Like Protein Tyrosine Phosphatases, Class 7 / Q000737:chemistry*; D053838:Scattering, Small Angle; D013816:Thermodynamics; D014961:X-Ray Diffraction
D048308:Mitogen-Activated Protein Kinase 14; C489930:PTPN5 protein, human; C513469:PTPRR protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D054634:Receptor-Like Protein Tyrosine Phosphatases, Class 7