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Molecular and Cellular Biology, May 2006, p. 3378-3389, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3378-3389.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cdc37 Interacts with the Glycine-Rich Loop of Hsp90 Client Kinases

Kazuya Terasawa,1 Katsuhiko Yoshimatsu,1 Shun-ichiro Iemura,2 Tohru Natsume,2 Keiji Tanaka,3 and Yasufumi Minami1*

Department of Biophysics and Biochemistry, and Undergraduate Program for Bioinformatics and Systems Biology, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan,1 National Institute of Advanced Industrial Science and Technology, Biological Information Research Center, Kohtoh-ku, Tokyo 135-0064, Japan,2 Laboratory of Frontier Science, Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan3

Received 1 December 2005/ Returned for modification 19 December 2005/ Accepted 10 February 2006

Recently, we identified a client-binding site of Cdc37 that is required for its association with protein kinases. Phage display technology and liquid chromatography-tandem mass spectrometry (which identifies a total of 33 proteins) consistently identify a unique sequence, GXFG, as a Cdc37-interacting motif that occurs in the canonical glycine-rich loop (GXGXXG) of protein kinases, regardless of their dependence on Hsp90 or Cdc37. The glycine-rich motif of Raf-1 (GSGSFG) is necessary for its association with Cdc37; nevertheless, the N lobe of Raf-1 (which includes the GSGSFG motif) on its own cannot interact with Cdc37. Chimeric mutants of Cdk2 and Cdk4, which differ sharply in their affinities toward Cdc37, show that their C-terminal portions may determine this difference. In addition, a nonclient kinase, the catalytic subunit of cyclic AMP-dependent protein kinase, interacts with Cdc37 but only when a threonine residue in the activation segment of its C lobe is unphosphorylated. Thus, although a region in the C termini of protein kinases may be crucial for accomplishing and maintaining their interaction with Cdc37, we conclude that the N-terminal glycine-rich loop of protein kinases is essential for physically associating with Cdc37.

* Corresponding author. Mailing address: Department of Biophysics and Biochemistry, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 133-0033, Japan. Phone and fax: 81-48-268-7274. E-mail: yminami{at}biochem.s.u-tokyo.ac.jp.

Molecular and Cellular Biology, May 2006, p. 3378-3389, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3378-3389.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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