Sci. Signal., 18 August 2009
SH2 Domains Getting a Second Grip
John F. Foley
Science Signaling, AAAS, Washington, DC 20005, USA
Binding of Src homology 2 (SH2) domain–containing proteins, such as phospholipase C– (PLC-), to phosphorylated tyrosine (pTyr) residues in activated receptor tyrosine kinases (RTKs), such as fibroblast growth factor receptor 1 (FGFR1), is critical to the activity of RTKs. Peptide-binding experiments have identified the specific targets of many SH2 domains; however, their binding affinities for these peptides are not very strong, suggesting that other sites might be involved in interactions between SH2 domains and RTKs in vivo. Bae et al. solved the crystal structure of the phosphorylated tyrosine kinase domain and C-terminal region of FGFR1 (FGFR1-3P) bound to a fragment of PLC- containing its N-SH2 and C-SH2 domains. (Although both domains can bind to an FGFR1-specific, pTyr-containing peptide, only N-SH2 binds to the corresponding region of the FGFR1 protein.) The authors found that, in addition to binding to FGFR1-3P through its canonical pTyr-binding site, the N-SH2 domain also bound to another region of FGFR1-3P that did not contain a pTyr. Binding experiments showed that the affinity of N-SH2 for FGFR1-3P was 10 to 70 times as high as that of the N-SH2 or C-SH2 domain for the corresponding peptide. Mutating residues in the region of FGFR1-3P targeted by the second binding site of N-SH2 reduced the overall affinity of the domain for FGFR1-3P. Experiments in transfected cells showed that mutation of these same residues of FGFR1-3P blocked FGF-dependent recruitment and activation of PLC- almost as effectively as did mutating the pTyr residue targeted by the canonical region of the N-SH2 domain. Together, these data suggest a mechanism whereby SH2 domain–containing proteins may selectively bind to target RTKs in vivo.
J. H. Bae, E. D. Lew, S. Yuzawa, F. Tomé, I. Lax, J. Schlessinger, The selectivity of receptor tyrosine kinase signaling is controlled by a secondary SH2 domain binding site. Cell 138, 514–524 (2009). [PubMed]
Citation: J. F. Foley, Getting a Second Grip. Sci. Signal. 2, ec271 (2009).
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