Activation loop dynamics in p38 MAPKs

RAMIRO RODRIGUEZ; DARDO FERREIRO; MARCELO MARTI; A.G. TURJANSKI

Quilmes, Buenos Aires, Argentina

Congreso; Primer Congreso de la Sociedad Argenitna de Bioinformática; 2010

Sociedad Argentina de Bioinformática yBiología Computacional

Mitogen-activated protein kinases (MAPKs) are serin-threonin kinases that participate in signal transduction pathways. p38 MAPKs have four isoforms (p38á, p38â, p38ã, and p38ä) which are involved in multiple cellular functions such as proliferation, differentiation, survival and migration. MAPK Kinases phosphorylate p38s in the dual-phosphorylation motif, Thr-Gly-Tyr, located in their activation loop, which induces a conformational change that increases ATP binding affinity and catalytic activity. By performing Molecular Dynamics Simulations we studied the conformations of the activation loop. We found a new conformation, termed closed, that could be involved in the autophosphorylation of p38. We calculated the free energy change and the interconversion mechanism between the open, with loop exposed to the solvent, and the closed conformation. As the mechanism of autophoshporylation is unknown our work can help to elucidate how MAPK get activated in the abscence of external stimuli.