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Determination of the substrate-docking site of protein tyrosine kinase C-terminal Src kinase

, : Determination of the substrate-docking site of protein tyrosine kinase C-terminal Src kinase. Proceedings of the National Academy of Sciences of the United States of America 100(25): 14707-14712

Protein tyrosine kinases (PTK) are key enzymes of mammalian signal transduction. For the fidelity of signal transduction, each PTK phosphorylates only one or a few proteins on specific Tyr residues. Substrate specificity is thought to be mediated by PTK-substrate docking interactions and recognition of the phosphorylation site sequence by the kinase active site. However, a substrate-docking site has not been determined on any PTK. C-terminal Src kinase (Csk) is a PTK that specifically phosphorylates Src family kinases on a C-terminal Tyr. In this study, by sequence alignment and site-specific mutagenesis, we located a substrate-docking site on Csk. Mutations in the docking site disabled Csk to phosphorylate, regulate, and complex with Src but only moderately affected its general kinase activity. A peptide mimicking the docking site potently inhibited (IC50 = 21 mM) Csk phosphorylation of Src but only moderately inhibited (IC50 = 422 mM) its general kinase activity. Determination of the substrate-docking site provides the structural basis of substrate specificity in Csk and a model for understanding substrate specificity in other PTKs. Reprinted by permission of the publisher.


PMID: 14657361

DOI: 10.1073/pnas.2534493100

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