jp5013297_si_001.pdf (2.69 MB)
Molecular Dynamics of the Proline Switch and Its Role in Crk Signaling
journal contribution
posted on 2015-12-17, 01:54 authored by Junchao Xia, Ronald M. LevyThe Crk adaptor proteins play a central
role as a molecular timer
for the formation of protein complexes including various growth and
differentiation factors. The loss of regulation of Crk results in
many kinds of cancers. A self-regulatory mechanism for Crk was recently
proposed, which involves domain–domain rearrangement. It is
initiated by a cis–trans isomerization of a specific proline
residue (Pro238 in chicken Crk II) and can be accelerated by Cyclophilin
A. To understand how the proline switch controls the autoinhibition
at the molecular level, we performed large-scale molecular dynamics
and metadynamics simulations in the context of short peptides and
multidomain constructs of chicken Crk II. We found that the equilibrium
and kinetic properties of the macrostates are regulated not only by
the local environments of specified prolines but also by the global
organization of multiple domains. We observe the two macrostates (cis
closed/autoinhibited and trans open/uninhibited) consistent with NMR
experiments and predict barriers. We also propose an intermediate
state, the trans closed state, which interestingly was reported to
be a prevalent state in human Crk II. The existence of this macrostate
suggests that the rate of switching off the autoinhibition by Cyp
A may be limited by the relaxation rate of this intermediate state.