title: Proline cis-trans isomerization controls autoinhibition of a signaling protein.
abstract: Autoinhibition is being widely used in nature to repress otherwise constitutive protein activities and is typically regulated by extrinsic factors. Here we show that autoinhibition can be controlled by an intrinsic intramolecular switch afforded by prolyl cis-trans isomerization. We find that a proline on the linker tethering the two SH3 domains of the Crk adaptor protein interconverts between the cis and trans conformation. In the cis conformation, the two SH3 domains interact intramolecularly, thereby forming the basis of an autoinhibitory mechanism. Conversely, in the trans conformation Crk exists in an extended, uninhibited conformation that is marginally populated but serves to activate the protein upon ligand binding. Interconversion between the cis and trans, and, hence, of the autoinhibited and activated conformations, is accelerated by the action of peptidyl-prolyl isomerases. Proline isomerization appears to make an ideal switch that can regulate the kinetics of activation, thereby modulating the dynamics of signal response.
authors.affiliation: Department of Chemistry, Rutgers University, Newark, NJ 07102, USA.
authors.forename: Paramita
authors.initials: P
authors.lastname: Sarkar
authors.forename: Charles
authors.initials: C
authors.lastname: Reichman
authors.forename: Tamjeed
authors.initials: T
authors.lastname: Saleh
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Birge
authors.forename: Charalampos G
authors.initials: CG
authors.lastname: Kalodimos
mesh_terms: D000591:Amino Acid Isomerases / Q000502:physiology; D000818:Animals; D002645:Chickens; D007536:Isomerism; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D019906:Nuclear Magnetic Resonance, Biomolecular; D011392:Proline / Q000737:chemistry*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D050737:Proto-Oncogene Proteins c-crk / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D050737:Proto-Oncogene Proteins c-crk; D011392:Proline; D000591:Amino Acid Isomerases