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J. Biol. Chem., Vol. 281, Issue 41, 30768-30781, October 13, 2006

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The Last 10 Amino Acid Residues beyond the Hydrophobic Motif Are Critical for the Catalytic Competence and Function of Protein Kinase C^*

Sui Sum Yeong¹, Yimin Zhu¹, Derek Smith, Chandra Verma^¶, Wee Guan Lim, Bee Jen Tan, Qiu Tian Li, Nam Sang Cheung, Minnie Cai^||, Yi-Zhun Zhu^**, Shu-Feng Zhou, Seng-Lai Tan, and Wei Duan^¶¶2

From the Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Bioinformatics Institute, 30 Biopolis Street, Singapore 138671, the ^¶Department of Biological Sciences, National University of Singapore, Science Drive 2, Singapore 117546, ^||Temasek Life Sciences Laboratory, 1 Research Link, Singapore 117604, ^**Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 200032, China, Department of Pharmacy, Faculty of Science, National University of Singapore, Science Drive 4, Singapore 117543, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana 46285, and ^¶¶Institute of Biotechnology, Deakin University, Victoria 3216, Australia

The segment C-terminal to the hydrophobic motif at the V5 domain of protein kinase C (PKC) is the least conserved both in length and in amino acid identity among all PKC isozymes. By generating serial truncation mutants followed by biochemical and functional analyses, we show here that the very C terminus of PKC is critical in conferring the full catalytic competence to the kinase and for transducing signals in cells. Deletion of one C-terminal amino acid residue caused the loss of 60% of the catalytic activity of the mutant PKC, whereas deletion of 10 C-terminal amino acid residues abrogated the catalytic activity of PKC in immune complex kinase assays. The PKC C-terminal truncation mutants were found to lose their ability to activate mitogen-activated protein kinase, to rescue apoptosis induced by the inhibition of endogenous PKC in COS cells, and to augment melatonin-stimulated neurite outgrowth. Furthermore, molecular dynamics simulations revealed that the deletion of 1 or 10 C-terminal residues results in the deformation of the V5 domain and the ATP-binding pocket, respectively. Finally, PKC immunoprecipitated using an antibody against its C terminus had only marginal catalytic activity compared with that of the PKC immunoprecipitated by an antibody against its N terminus. Therefore, the very C-terminal tail of PKC is a novel determinant of the catalytic activity of PKC and a promising target for selective modulation of PKC function. Molecules that bind preferentially to the very C terminus of distinct PKC isozymes and suppress their catalytic activity may constitute a new class of selective inhibitors of PKC.

Received for publication, October 17, 2005 , and in revised form, July 27, 2006.

^* This work was supported by grants from the National Medical Research Council, A^*STAR (Biomedical Research Council), Singapore, and Deakin University (to W. D.). 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 61-3-5260-3465; Fax: 61-3-5227-2175; E-mail: wduan{at}deakin.edu.au.

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