Structural basis for regulation of the Crk signaling protein by a proline switch

Paramita Sarkar, Tamjeed Saleh, Shiou Ru Tzeng, Raymond B. Birge, Charalampos G. Kalodimos

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)51-57
Number of pages7
JournalNature Chemical Biology
Issue number1
StatePublished - Jan 2011
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the US National Institutes of Health (GM80308 to C.G.K.).


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