Structural basis for regulation of the Crk signaling protein by a proline switch.
Proline switches, controlled by cis-trans isomerization, have emerged as a particularly effective regulatory mechanism in a wide range of biological processes. Here we report the structures of both the cis and trans conformers of a proline switch in the Crk signaling protein. Proline isomerization toggles Crk between two conformations: an autoinhibitory conformation, stabilized by the intramolecular association of two tandem SH3 domains in the cis form, and an uninhibited, activated conformation promoted by the trans form. In addition to acting as a structural switch, the heterogeneous proline recruits cyclophilin A, which accelerates the interconversion rate between the isomers, thereby regulating the kinetics of Crk activation. The data provide atomic insight into the mechanisms that underpin the functionality of this binary switch and elucidate its remarkable efficiency. The results also reveal new SH3 binding surfaces, highlighting the binding versatility and expanding the noncanonical ligand repertoire of this important signaling domain.
Department of Chemistry & Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
Paramita
P
Sarkar
Tamjeed
T
Saleh
Shiou-Ru
SR
Tzeng
Raymond B
RB
Birge
Charalampos G
CG
Kalodimos
D021984:Cyclophilin A / Q000737:chemistry / Q000378:metabolism; D007536:Isomerism; D008024:Ligands; D011392:Proline / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D050737:Proto-Oncogene Proteins c-crk / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D018909:src Homology Domains / Q000187:drug effects
C485285:CRK protein, human; D008024:Ligands; D050737:Proto-Oncogene Proteins c-crk; D011392:Proline; D021984:Cyclophilin A