Activation of the Sire-family tyrosine kinase Hck by SH3 domain displacement

Ismail Moarefi, Michelle LaFevre-Bernt, Frank Sicheri, Morgan Huse, Chi-Hon Lee, John Kuriyan and W. Todd Miller
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Ismail Moarefi: The Rockefeller University
Michelle LaFevre-Bernt: State University of New York at Stony Brook
Frank Sicheri: The Rockefeller University
Morgan Huse: The Rockefeller University
Chi-Hon Lee: The Rockefeller University
John Kuriyan: The Rockefeller University
W. Todd Miller: State University of New York at Stony Brook

Nature, 1997, vol. 385, issue 6617, 650-653

Abstract: Abstract The protein Hck is a member of the Src family of non-receptor tyrosine kinases which is preferentially expressed in haematopoietic cells of the myeloid and B-lymphoid lineages1,2. Src kinases are inhibited by tyrosine-phosphorylation at a carboxy-terminal site3–9. The SH2 domains of these enzymes play an essential role in this regulation by binding to the tyrosine-phosphorylated tail8–11. The crystal structure of the downregulated form of Hck has been determined12 and reveals that the SH2 domain regulates enzymatic activity indirectly; intramolecular interactions between the SH3 and catalytic domains appear to stabilize an inactive form of the kinase. Here we compare the roles of the SH2 and SH3 domains in modulating the activity of Hck in an investigation of the C-terminally phosphorylated form of the enzyme. We show that addition of the HIV-1 Nef protein, which is a high-affinity ligand for the Hck SH3 domain, to either the downregulated or activated form of Hck causes a large increase in Hck catalytic activity. The intact SH3-binding motif in Nef is crucial for Hck activation. Our results indicate that binding of the Hck SH3 domain by Nef causes a more marked activation of the enzyme than does binding of the SH2 domain, suggesting a new mechanism for regulation of the activity of tyrosine kinases.

Date: 1997
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DOI: 10.1038/385650a0

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