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Papers In Press, published online ahead of print December 28, 2004
J. Biol. Chem, 10.1074/jbc.M411736200
Submitted on October 15, 2004
Revised on December 9, 2004
Accepted on December 27, 2004

Phosphoryl transfer step in the C-terminal Src kinase controls Src recognition

Scot Lieser, Caitlin Shindler, Brandon E. Aubol, Sungsoo Lee, Gongqin Sun, and Joseph A. Adams

Department of Pharmacology, Univ. of California, San Diego, La Jolla, CA 92093-0728

Corresponding Author: joeadams{at}ucsd.edu

All members of the Src family of nonreceptor protein tyrosine kinases are phosphorylated and subsequently down-regulated by the C-terminal Src kinase, Csk. While the recognition of Src protein substrates is essential for a diverse set of signaling events linked to cellular growth and differentiation, the factors controlling this critical protein-protein interaction are not well known. To understand how Csk recognizes Src, the chemical/physical events that modulate apparent substrate affinity and turnover were investigated. Src is phosphorylated in a biphasic manner in rapid quench flow experiments suggesting that the phosphoryl transfer step is fast, highly favorable and does not limit overall turnover. As opposed to other kinase-substrate pairs, turnover is not limited by the physical release of ADP based on stopped-flow fluorescence and catalytic trapping experiments, suggesting that other steps control net phosphorylation. The Kd for Src is considerably larger than the Km based on single turnover kinetic and equilibrium sedimentation experiments. Taken together, the data are consistent with a mechanism whereby Csk achieves a low Km for the substrate Src not by stabilizing protein-protein interactions but rather by facilitating a fast phosphoryl transfer step. In this manner, the phosphoryl transfer step functions as a chemical clamp facilitating substrate recognition.


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