Editors' ChoiceBiochemistry

Multifunctional SH2 Domains

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Science Signaling  09 Sep 2008:
Vol. 1, Issue 36, pp. ec321
DOI: 10.1126/scisignal.136ec321

Src homology 2 (SH2) domains interact with sites on proteins that contain phosphotyrosine residues. The SH2 domains of cytoplasmic tyrosine kinases like Src have an important and well-defined role in intramolecular interactions that keep 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 in tyrosine kinases can alternatively act to enhance activity of kinases through cooperative interactions with the catalytic domain of the kinase and with substrate proteins. The authors solved the crystal structures of a portion of Fes that contains the SH2 domain and kinase domain and that was either phosphorylated or not on 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. The authors then extended the analysis to the pro-oncogenic tyrosine kinase c-Abl to show that a similar mechanism occurs in other members of the cytoplasmic tyrosine kinase family, including some in which the SH2 domain functions in autoinhibition, although the molecular detail of the interaction is different. 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.

P. Filippakopoulos, M. Kofler, O. Hantschel, G. D. Gish, F. Grebien, E. Salah, P. Neudecker, L. E. Kay, B. E. Turk, G. Superti-Furga, T. Pawson, S. Knapp, Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation. Cell 134, 793-803 (2008). [PubMed]

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