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J. Biol. Chem., Vol. 277, Issue 17, 14351-14354, April 26, 2002
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From the The carboxyl-terminal Src kinase (Csk) is an
indispensable negative regulator for the Src family tyrosine kinases
(SFKs) that play pivotal roles in various cell signalings. To
understand the molecular basis of the Csk-mediated regulation of SFKs,
we elucidated the crystal structure of full-length Csk. The Csk crystal
consists of six molecules classified as active or inactive states
according to the coordinations of catalytic residues. Csk assembles the SH2 and SH3 domains differently from inactive SFKs, and their binding
pockets are oriented outward enabling the intermolecular interaction.
In active molecules, the SH2-kinase and SH2-SH3 linkers are tightly
stuck to the N-lobe of the kinase domain to stabilize the active
conformation, and there is a direct linkage between the SH2 and the
kinase domains. In inactive molecules, the SH2 domains are rotated
destroying the linkage to the kinase domain. Cross-correlation matrices
for the active molecules reveal that the SH2 domain and the N-lobe of
the kinase domain move as a unit. These observations suggest that Csk
can be regulated through coupling of the SH2 and kinase domains and
that Csk provides a novel built-in activation mechanism for cytoplasmic
tyrosine kinases.
Institute for Protein Research, Osaka
University, 3-2 Yamadaoka and Research Institute for Microbial
Diseases, Osaka University, 3-1 Yamadaoka, Suita,
Osaka 565-0871, Japan
The atomic coordinates and the structure factors (code 1K9A) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
§ Present address: National Institute of Livestock and Grassland Science 2, Ikenodai, Kukizaki, Inashiki, Ibaraki 305-0901, Japan. ¶ To whom correspondence may be addressed. E-mail: okadam@ biken.osaka-u.ac.jp or atsushi@protein.osaka-u.ac.jp.This article has been cited by other articles:
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