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Proline isomerization preorganizes the Itk SH2 domain for binding the Itk SH3 domain
Journal of Molecular Biology
  • Andrew J. Severin, Iowa State University
  • Raji E. Joseph, Iowa State University
  • Scott E. Boyken, Iowa State University
  • D. Bruce Fulton, Iowa State University
  • Amy H. Andreotti, Iowa State University
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Accepted Manuscript
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We report here the NMR-derived structure of the binary complex formed by the interleukin-2 tyrosine kinase (Itk) Src homology 3 (SH3) and Src homology 2 (SH2) domains. The interaction is independent of both a phosphotyrosine motif and a proline-rich sequence, the classical targets of the SH2 and SH3 domains, respectively. The Itk SH3/SH2 structure reveals the molecular details of this nonclassical interaction and provides a clear picture for how the previously described prolyl cis/trans isomerization present in the Itk SH2 domain mediates SH3 binding. The higher-affinity cis SH2 conformer is preorganized to form a hydrophobic interface with the SH3 domain. The structure also provides insight into how autophosphorylation in the Itk SH3 domain might increase the affinity of the intermolecular SH3/SH2 interaction. Finally, we can compare this Itk complex with other examples of SH3 and SH2 domains engaging their ligands in a nonclassical manner. These small binding domains exhibit a surprising level of diversity in their binding repertoires.

This article is from Journal of Molecular Biology 387 (2009): 726–743, doi:10.1016/j.jmb.2009.02.012. Posted with permission.

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Elsevier Ltd.
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Citation Information
Andrew J. Severin, Raji E. Joseph, Scott E. Boyken, D. Bruce Fulton, et al.. "Proline isomerization preorganizes the Itk SH2 domain for binding the Itk SH3 domain" Journal of Molecular Biology Vol. 387 Iss. 3 (2009) p. 726 - 743
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