Sci. STKE, 21 March 2000
Structural Biology Checking Out Chk1
In the presence of DNA damage, the protein kinase Chk1 can effect cell cycle arrest. Chen et al. determined the crystal structure of the Chk1 kinase domain (Chk1KD), and have uncovered some of its regulatory mechanisms. In the presence or absence of the nonhydrolyzable analog AMP-PNP, no conformational change was observed in the Chk1KD ATP binding site, catalytic residues, or activation loop. Therefore, the conformation of Chk1KD approximates its activated ATP-bound state, and Chk1 does not appear to require activation loop phosphorylation before activity. The authors determined that the regulation of Chk1 may be controlled by its COOH-terminal region; the kinase activity of Chk1KD was 20 times that of full-length Chk1, and autophosphorylation of full-length Chk1 did not inherently affect its kinase activity. The authors speculate on the role of the COOH-terminus in autoinhibition. The crystal structure of the linker region between the kinase domain and the COOH-terminal region indicates that, instead of the typical COOH-terminal autoinhibitory mechanism used by many kinases, involving occlusion of substrate binding, the COOH-terminal region of Chk1 may keep the kinase domain in an open conformation.
Chen, P., Luo, C., Deng, Y., Ryan, K., Register, J., Margosiak, S., Tempczyk-Russell, A., Nguyen, B., Myers, P., Lundgren, K., Kan, C.-C., and O'Connor, P.M. (2000) The 1.7 crystal structure of human cell cycle checkpoint kinase Chk1: Implications for Chk1 regulation. Cell 100:681-692. [Online Journal]
Citation: Checking Out Chk1. Sci. STKE 2000, tw10 (2000).
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