SH2 Uninhibited

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Science  26 Sep 2008:
Vol. 321, Issue 5897, pp. 1743
DOI: 10.1126/science.321.5897.1743c

Src-homology 2 (SH2) domains of cytoplasmic tyrosine kinases have an important and well-defined role in keeping such kinases in an autoinhibited conformation. Filippakopoulos et al. studied the human cytoplasmic tyrosine kinase Fes, which lacks this autoinhibitory interaction, and uncovered molecular details of how SH2 domains can alternatively act to enhance activity. The authors solved crystal structures of a portion of Fes containing the SH2 domain and kinase domain, with and without phosphorylation of the kinase activation segment. This fragment was bound in complexes with a substrate peptide and an ATP-mimetic kinase inhibitor. Mutagenesis experiments confirmed that the visualized interaction of the SH2 domain with the kinase domain was necessary to stabilize the active conformation of the enzyme. Analysis of synthetic substrates with or without phosphorylated SH2 domain-binding sites also showed the importance of the SH2 domain in substrate recruitment. Extending the analysis to the pro-oncogenic tyrosine kinase c-Abl showed that a similar mechanism occurs in other members of the cytoplasmic tyrosine kinase family. The authors point out that such coupling of substrate recognition to kinase activation may contribute to selectivity of such kinases so that they act only on the appropriate substrates in vivo.— LBR

Cell 134, 793 (2008).

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