Prolyl isomerization as a molecular memory in the allosteric regulation of the signal adapter protein c-CrkII [Protein Structure and Folding]
December 8th, 2014 by Schmidpeter, P. A. M., Schmid, F. X.
c-CrkII is a central signal adapter protein. A domain opening/closing reaction between its N-terminal and C-terminal SH3 domains (SH3N and SH3C, respectively) controls signal propagation from upstream tyrosine kinases to downstream targets. In chicken but not in human c-CrkII, opening/closing is coupled with cis/trans isomerization at Pro238 in SH3C. Here, we used advanced double-mixing experiments and kinetic simulations to uncover dynamic domain interactions in c-CrkII, to elucidate how they are linked with cis/trans isomerization, and how this regulates substrate binding to SH3N. Pro238 trans → cis isomerization is not a simple on/off switch, but converts chicken c-CrkII from a high-affinity to a low-affinity form. We present a double-box model that describes c-CrkII as an allosteric system consisting of an open, high-affinity R state and a closed, low-affinity T state. Coupling of the T-R transition with an intrinsically slow prolyl isomerization provides c-CrkII with a kinetic memory and possibly functions as a molecular attenuator during signal transduction.