Identification of N-Terminal Lobe Motifs that Determine the Kinase Activity of the Catalytic Domains and Regulatory Strategies of Src and Csk Protein Tyrosine Kinases

Authors

Kezhen Huang, University of Rhode Island
Yue-Hao Wang, University of Rhode Island
Alex Brown, University of Rhode Island
Gongqin Sun, University of Rhode IslandFollow

Document Type

Article

Date of Original Version

2009

Department

Cell & Molecular Biology

Abstract

Csk and Src protein tyrosine kinases are structurally homologous but use opposite regulatory strategies. The isolated catalytic domain of Csk is intrinsically inactive and is activated by interactions with the regulatory Src homology 3 (SH3) and SH2 domains, while the isolated catalytic domain of Src is intrinsically active and is suppressed by interactions with the regulatory SH3 and SH2 domains. The structural basis for why one isolated catalytic domain is intrinsically active while the other is inactive is not clear. In this study, we identified structural elements in the N-terminal lobe of the catalytic domain that render the Src catalytic domain active. These structural elements include the α-helix C region, a β turn between the β4 and β5 strands, and an Arg residue at the beginning of the catalytic domain. These three motifs interact with one another to activate the Src catalytic domain, but the equivalent motifs in Csk directly interact with the regulatory domains that are important for Csk activation. The Src motifs can be grafted to the Csk catalytic domain to obtain an active Csk catalytic domain. These results, together with available Src and Csk tertiary structures, reveal an important structural switch that determines the kinase activity of a catalytic domain and dictates the regulatory strategy of a kinase.

Citation/Publisher Attribution

Huang, K., Wang, Y.-H., Brown, A., & Sun, G. (2009). Identification of N-Terminal Lobe Motifs that Determine the Kinase Activity of the Catalytic Domains and Regulatory Strategies of Src and Csk Protein Tyrosine Kinases. Journal of Molecular Biology, 386(4), 1066-1077. doi: 10.1016/j.jmb.2009.01.012

Available at: https://doi.org/10.1016/j.jmb.2009.01.012

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