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. [Display omitted] •The p38α:PTPSL interaction is confined mainly to the KIM binding site•The p38α:PTPSL complex adopts an extended conformation•The STEP catalytic domain interacts with a p38α binding site•The p38α:STEP resting and active states have distinct conformations To understand the molecular regulation of p38α, Francis et al. determine the structural basis of p38α binding by the tyrosine phosphatases PTPSL and STEP. Although PTPSL and STEP belong to the same family of regulatory proteins, they interact differently with p38α, explaining their different activities toward p38α.