Kinase Activation by Small Conformational Changes

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.