title: Prolyl isomerization as a molecular memory in the allosteric regulation of the signal adapter protein c-CrkII.
abstract: c-CrkII is a central signal adapter protein. A domain opening/closing reaction between its N- and C-terminal Src homology 3 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 Pro-238 in SH3C. Here, we used advanced double-mixing experiments and kinetic simulations to uncover dynamic domain interactions in c-CrkII and to elucidate how they are linked with cis/trans isomerization and how this regulates substrate binding to SH3N. Pro-238 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.
authors.affiliation: From the Laboratorium für Biochemie und Bayreuther Zentrum für Molekulare Biowissenschaften, Universität Bayreuth, 95440 Bayreuth, Germany.
authors.forename: Philipp A M
authors.initials: PA
authors.lastname: Schmidpeter
authors.affiliation: From the Laboratorium für Biochemie und Bayreuther Zentrum für Molekulare Biowissenschaften, Universität Bayreuth, 95440 Bayreuth, Germany fx.schmid@uni-bayreuth.de.
authors.forename: Franz X
authors.initials: FX
authors.lastname: Schmid
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002645:Chickens; D006801:Humans; D017510:Protein Folding; D050737:Proto-Oncogene Proteins c-crk / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D018909:src Homology Domains / Q000502:physiology
chemical_list: D050737:Proto-Oncogene Proteins c-crk
keywords: Adaptor Protein; Allosteric Regulation; Biophysics; Native State Prolyl Isomerization; Protein Folding; Sequential Mixing Stopped Flow; Src Homology 3 Domain (SH3 Domain); c-CrkII