The TAB1-p38α complex aggravates myocardial injury and can be targeted by small molecules

• DOI: 10.1172/jci.insight.121144
• Publication Date: 2018-08-22T15:01:09Z
• Authors: Gian F. De Nicola; Rekha Bassi; Charlie Nichols; Mariana Fernandez...; Pelin Arabacilar ...; Dibesh Thapa; Rhys Anderson; Eva Denise Martin; Sharwari Verma; Jens Kleinjung; Adam Laing; Jonathan P. Hutch...; Philip Eaton; James Clark; Michael S. Marber
• Keywords: Male; 0301 basic medicine; Cardiology; Myocardial Infarction; 610; Adamantane; Mice, Transgenic; Therapeutics; Crystallography, X-Ray; Cell Line; Mitogen-Activated Protein Kinase 14; Mice; 03 medical and health sciences; Protein kinases; Animals; Humans; Protein Interaction Domains and Motifs; Gene Knock-In Techniques; Phosphorylation; Adaptor Proteins, Signal Transducing; Pharmacology; Myocardium; 540; Disease Models, Animal; HEK293 Cells; Mutation; Female; Structural biology; Research Article; Protein Binding

Inhibiting MAPK14 (p38α) diminishes cardiac damage in myocardial ischemia. During ischemia, p38α interacts with TAB1, a scaffold protein, which promotes autoactivation; active (pp38α) then transphosphorylates TAB1. Previously, we solved the X-ray structure of p38α-TAB1 (residues 384-412) complex. Here, further characterize interaction by solving pp38α-TAB1 1-438) complex state. Based on this information, created global knock-in (KI) mouse substitution 4 residues TAB1 that show are required for docking onto p38α. Whereas ablating or resulted early embryonal lethality, TAB1-KI mice were viable and had no appreciable alteration their lymphocyte repertoire transcriptional profile; nonetheless, following vivo regional infarction volume was significantly reduced transphosphorylation disabled. Unexpectedly, activation during ischemia only mildly attenuated hearts. We also identified group fragments able to disrupt between conclude 2 proteins can be targeted small molecules. The data reveal it is possible selectively inhibit signaling downstream attenuate ischemic injury.