Conformational Equilibrium
of N‑Myristoylated
cAMP-Dependent Protein Kinase A by Molecular Dynamics Simulations
- Publication date
- Publisher
Abstract
The catalytic subunit of protein kinase A (PKA-C) is
subject to
several post- or cotranslational modifications that regulate its activity
both spatially and temporally. Among those, N-myristoylation increases
the kinase affinity for membranes and might also be implicated in
substrate recognition and allosteric regulation. Here, we investigated
the effects of N-myristoylation on the structure, dynamics, and conformational
equilibrium of PKA-C using atomistic molecular dynamics simulations.
We found that the myristoyl group inserts into the hydrophobic pocket
and leads to a tighter packing of the A-helix against the core of
the enzyme. As a result, the conformational dynamics of the A-helix
are reduced and its motions are more coupled with the active site.
Our simulations suggest that cation−π interactions among
W30, R190, and R93 are responsible for coupling these motions. Two
major conformations of the myristoylated N-terminus are the most populated:
a long loop (LL conformation), similar to Protein Data Bank (PDB)
entry 1CMK,
and a helix–turn–helix structure (HTH conformation),
similar to PDB entry 4DFX, which shows stronger coupling between the conformational dynamics
observed at the A-helix and active site. The HTH conformation is stabilized
by S10 phosphorylation of the kinase via ionic interactions between
the protonated amine of K7 and the phosphate group on S10, further
enhancing the dynamic coupling to the active site. These results support
a role of N-myristoylation in the allosteric regulation of PKA-C