Proline cis-trans Isomerization Controls Autoinhibition of a Signaling Protein

Paramita Sarkar, Charles Reichman, Tamjeed Saleh, Raymond B. Birge, Charalampos G. Kalodimos

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)413-426
Number of pages14
JournalMolecular Cell
Volume25
Issue number3
DOIs
StatePublished - Feb 9 2007
Externally publishedYes

Bibliographical note

Funding Information:
We thank Onyi Uchime, Leong Cho, and Neil Kausal for assistance with sample preparation. Plasmids encoding CypA and His 6 -CypA were gifts of W. Sundquist and C. Freund. This work was supported by a Busch Biomedical grant (to C.G.K.) and GM-55740 grant (to R.B.B.).

Keywords

  • SIGNALING

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