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Substrate Recognition of PLCγ1 via a Specific Docking Surface on Itk
Journal of Molecular Biology
  • Qian Xie, Iowa State University
  • Raji E. Joseph, Iowa State University
  • D. Bruce Fulton, Iowa State University
  • Amy H. Andreotti, Iowa State University
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Itk (interleukin-2 inducible T cell kinase) is a non-receptor protein tyrosine kinase expressed primarily in T cells. Itk catalyzes phosphorylation on tyrosine residues within a number of its natural substrates, including the well-characterized Y783 of PLCγ1. However, the molecular mechanisms Itk exploits to recognize its substrates are not completely understood. We have previously identified a specific docking interaction between the kinase domain of Itk and the Cterminal Src homology 2 (SH2C) domain of PLCγ1 that promotes substrate specificity for this enzyme/substrate pair. In the current study, we identify and map the interaction surface on the Itk kinase domain as an acidic patch centered on the G helix. Mutation of the residues on and adjacent to the G helix within the Itk kinase domain impairs the catalytic efficacy of PLCγ1 substrate phosphorylation by specifically altering the protein–protein interaction interface and not the inherent catalytic activity of Itk. NMR titration experiments using a Btk (Bruton’s tyrosine kinase) kinase domain as a surrogate for the Itk kinase domain provide further support for an Itk/PLCγ1 SH2C interaction surrounding the G helix of the kinase domain. The work presented here provides structural insight into how the Itk kinase uses the G helix to single out Y783 of PLCγ1 for specific phosphorylation. Comparing these results to other well-characterized kinase/substrate systems suggests that the G helix is a general structural feature used by kinases for substrate recognition during signaling.

This is a manuscript of an article published as Xie, Qian, Raji E. Joseph, D. Bruce Fulton, and Amy H. Andreotti. "Substrate recognition of PLCγ1 via a specific docking surface on Itk." Journal of molecular biology 425, no. 4 (2013): 683-696. doi: 10.1016/j.jmb.2012.10.023. Posted with permission.

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Creative Commons Attribution-Noncommercial-No Derivative Works 4.0
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Elsevier Ltd
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Qian Xie, Raji E. Joseph, D. Bruce Fulton and Amy H. Andreotti. "Substrate Recognition of PLCγ1 via a Specific Docking Surface on Itk" Journal of Molecular Biology Vol. 425 Iss. 4 (2013) p. 683 - 696
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