Catalysis and Function of the p38α·MK2a Signaling Complex

The p38 mitogen-activated protein kinase (p38) pathway is required for the production of proinflammatory cytokines (TNFα and IL-1) that mediate the chronic inflammatory phases of several autoimmune diseases. Potent p38 inhibitors, such as the slow tight-binding inhibitor BIRB 796, have recently been reported to block the production of TNFα and IL-1β. Here we analyze downstream signaling complexes and molecular mechanisms, to provide new insight into the function of p38 signaling complexes and the development of novel inhibitors of the p38 pathway. Catalysis, signaling functions, and molecular interactions involving p38α and one of its downstream signaling partners, mitogen-activated protein kinase-activated protein kinase 2 (MK2), have been explored by steady-state kinetics, surface plasmon resonance, isothermal calorimetry, and stopped-flow fluorescence. Functional 1/1 signaling complexes (Kd = 1−100 nM) composed of activated and nonactivated forms of p38α and a splice variant of MK2 (MK2a) were characte...