p38γ Activation Triggers Dynamical Changes in Allosteric Docking Sites.

RAMIRO RODRIGUEZ-LIMARDO; DARDO N FERREIRO; ADRIAN E ROIRBERG; MARCELO A. MARTI; ADRIAN G TURJANSKI

BIOCHEMISTRY

AMER CHEMICAL SOC

Año: 2011 p. 1384 - 1395

0006-2960

ABSTRACT: Mitogen-activated protein kinases (MAPKs) are serine-threonine kinases that participate in signaltransduction pathways. p38 MAPKs have four isoforms (p38R, p38β, p38γ, and p38δ) which are involved inmultiple cellular functions such as proliferation, differentiation, survival, and migration. MAPK kinasesphosphorylate p38s in the dual-phosphorylation motif, Thr-Gly-Tyr, located in their activation loop, whichinduces a conformational change that increases ATP binding affinity and catalytic activity. Several workshave proposed that MAPK dynamics is a key factor in determining their function. However, we still do notunderstand the dynamical changes that lead to MAPK activation. In this work we have used moleculardynamics techniques to study the dynamical changes associated with p38γ activation, the only fully activeMAPK crystallized so far. We performed MD simulations of p38γ in three different states, fully active withATP, active without ATP, and inactive. We found that the dynamical fluctuations of the docking sites,important for protein-protein interactions, are regulated allosterically by changes in the active site.Interestingly, in the phosphorylated and ATP-bound states the whole protein dynamics lead to concertedmotions of whole protein domains in contrast to the inactive state. The binding/unbinding of ATPparticipates in the reorientation of the two domains and in the regulation of protein plasticity. Our studyshows that beyond the conformational changes associated with MAPK activation their correlated dynamicsare highly regulated by phosphorylation and ATP binding. This means that MAPK plasticity may have a rolein their catalytic activity, specificity, and protein-protein interactions and, therefore, in the outcome of thesignaling network.