Kinase Activation by Small Conformational Changes

BURASTERO OSVALDO; AHN, NATALIE G.; LOPEZ, ELIAS DANIEL; DEFELIPE, LUCAS A.; TURJANSKI, ADRIÁN G.; ARCON, JUAN PABLO; MARTI, MARCELO A.

JOURNAL OF CHEMICAL INFORMATION AND MODELING

AMER CHEMICAL SOC

Lugar: Washington; Año: 2019 vol. 60 p. 821 - 832

1549-9596

Protein kinases (PKs) are allosteric enzymesthat play an essential role in signal transduction by regulating avariety of key cellular processes. Most PKs suffer conformational rearrangements upon phosphorylation that stronglyenhance the catalytic activity. Generally, it involves themovement of the phosphorylated loop toward the active siteand the rotation of the whole C-terminal lobe. However, not all kinases undergo such a large configurational change: TheMAPK extracellular signal-regulated protein kinases ERK1 and ERK2 achieve a 50 000 fold increase in kinase activity with onlya small motion of the C-terminal region. In the present work, we used a combination of molecular simulation tools tocharacterize the conformational landscape of ERK2 in the active (phosphorylated) and inactive (unphosphorylated) states insolution in agreement with NMR experiments. We show that the chemical reaction barrier is strongly dependent on ATPconformation and that the ?active? low-barrier configuration is subtly regulated by phosphorylation, which stabilizes a key saltbridge between the conserved Lys52 and Glu69 belonging to helix-C and promotes binding of a second Mg ion. Our studyhighlights that the on−off switch embedded in the kinase fold can be regulated by small, medium, and large conformationalchanges.