info:eu-repo/semantics/article
Kinase Activation by Small Conformational Changes
Fecha
2019-11Registro en:
Lopez, Elias Daniel; Burastero, Osvaldo; Arcon, Juan Pablo; Defelipe, Lucas Alfredo; Ahn, Natalie G.; et al.; Kinase Activation by Small Conformational Changes; American Chemical Society; Journal of Chemical Information and Modeling; 60; 2; 11-2019; 821-832
1549-9596
CONICET Digital
CONICET
Autor
Lopez, Elias Daniel
Burastero, Osvaldo
Arcon, Juan Pablo
Defelipe, Lucas Alfredo
Ahn, Natalie G.
Marti, Marcelo Adrian
Turjanski, Adrian
Resumen
Protein kinases (PKs) are allosteric enzymes that play an essential role in signal transduction by regulating a variety of key cellular processes. Most PKs suffer conformational rearrangements upon phosphorylation that strongly enhance the catalytic activity. Generally, it involves the movement of the phosphorylated loop toward the active site and the rotation of the whole C-terminal lobe. However, not all kinases undergo such a large configurational change: The MAPK extracellular signal-regulated protein kinases ERK1 and ERK2 achieve a 50»000 fold increase in kinase activity with only a small motion of the C-terminal region. In the present work, we used a combination of molecular simulation tools to characterize the conformational landscape of ERK2 in the active (phosphorylated) and inactive (unphosphorylated) states in solution in agreement with NMR experiments. We show that the chemical reaction barrier is strongly dependent on ATP conformation and that the "active" low-barrier configuration is subtly regulated by phosphorylation, which stabilizes a key salt bridge between the conserved Lys52 and Glu69 belonging to helix-C and promotes binding of a second Mg ion. Our study highlights that the on-off switch embedded in the kinase fold can be regulated by small, medium, and large conformational changes.