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J. Biol. Chem., Vol. 280, Issue 27, 25780-25787, July 8, 2005

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Functional Diversity of Csk, Chk, and Src SH2 Domains due to a Single Residue Variation^*

Marina K. Ayrapetov, Nguyen Hai Nam, Guofeng Ye, Anil Kumar, Keykavous Parang, and Gongqin Sun¶

From the Departments of Cell and Molecular Biology and Biomedical Sciences, University of Rhode Island, Kingston, Rhode Island 02881

The C-terminal Src kinase (Csk) family of protein tyrosine kinases contains two members: Csk and Csk homologous kinase (Chk). Both phosphorylate and inactivate Src family kinases. Recent reports suggest that the Src homology (SH) 2 domains of Csk and Chk may bind to different phosphoproteins, which provides a basis for different cellular functions for Csk and Chk. To verify and characterize such a functional divergence, we compared the binding properties of the Csk, Chk, and Src SH2 domains and investigated the structural basis for the functional divergence. First, the study demonstrated striking functional differences between the Csk and Chk SH2 domains and revealed functional similarities between the Chk and Src SH2 domains. Second, structural analysis and mutagenic studies revealed that the functional differences among the three SH2 domains were largely controlled by one residue, Glu¹²⁷ in Csk, Ile¹⁶⁷ in Chk, and Lys²⁰⁰ in Src. Mutating these residues in the Csk or Chk SH2 domain to the Src counterpart resulted in dramatic gain of function similar to Src SH2 domain, whereas mutating Lys²⁰⁰ in Src SH2 domain to Glu (the Csk counterpart) resulted in loss of Src SH2 function. Third, a single point mutation of E127K rendered Csk responsive to activation by a Src SH2 domain ligand. Finally, the optimal phosphopeptide sequence for the Chk SH2 domain was determined. These results provide a compelling explanation for the functional differences between two homologous protein tyrosine kinases and reveal a new structure-function relationship for the SH2 domains.

Received for publication, April 13, 2005

^* This work was supported by American Cancer Society Grant RSG-04-247-01-CDD and National Institutes of Health Grant 1 P20 RR16457. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Cell and Molecular Biology, 117 Morrill Hall, 45 Lower College Rd., University of Rhode Island, Kingston, RI 02881. Tel.: 401-874-5937; Fax: 401-874-2202; E-mail: gsun{at}uri.edu.

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				M. K. Ayrapetov, Y.-H. Wang, X. Lin, X. Gu, K. Parang, and G. Sun Conformational Basis for SH2-Tyr(P)527 Binding in Src Inactivation J. Biol. Chem., August 18, 2006; 281(33): 23776 - 23784. [Abstract] [Full Text] [PDF]