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J. Biol. Chem., Vol. 278, Issue 24, 22056-22060, June 13, 2003

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A Transmembrane Segment Mimic Derived from Escherichia coli Diacylglycerol Kinase Inhibits Protein Activity^*

Anthony W. Partridge  , Roman A. Melnyk  , Dawn Yang ¶, James U. Bowie ¶ and Charles M. Deber  ||

From the Division of Structural Biology and Biochemistry, Research Institute, Hospital for Sick Children, Toronto, Ontario M5G 1X8 and the Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada, ^¶ Department of Chemistry and Biochemistry, UCLA-Department of Energy Laboratory of Structural Biology and Molecular Medicine, Los Angeles, California 90095-1570

The function of membrane proteins is inextricably linked to the proper packing and assembly of their independently helical transmembrane (TM) segments. Here we examined whether an externally added TM peptide analogue could specifically inhibit the function of the membrane protein from which it is derived by competing for native TM helix packing sites, thereby producing a non-functional peptide-protein complex. This hypothesis was tested using Lys-tagged peptides synthesized with sequences corresponding to the three TM segments of the homotrimeric Escherichia coli diacylglycerol kinase (DGK). The peptide corresponding to wild-type DGK TM-2 inhibited the protein's enzymatic activity in a dose-dependent manner through formation of an inactive pseudo-complex, whereas peptides derived from TM-1 and TM-3 were benign toward DGK structure/function. Also, substitution of a conserved residue (Glu-69) within the TM-2 peptide abolished these effects, demonstrating the strict sequence requirements for TM-2-mediated association. This strategy, coupled with the practical advantages of the water solubility of Lys-tagged TM peptides, may constitute an attractive approach for the design of therapeutic membrane protein modulators even in the absence of a high resolution structure.

Received for publication, October 18, 2002 , and in revised form, March 13, 2003.

^* This work was supported in part by grants from the Canadian Institutes of Health Research (CIHR) (to C. M. D.), the Natural Sciences and Engineering Research Council of Canada (NSERC) (to C. M. D.), and the National Institutes of Health (to J. U. B.). 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.

These authors contributed equally to this work and hold Canadian Institutes of Health Research Doctoral Awards.

^|| To whom correspondence should be addressed: Research Institute, Structural Biology & Biochemistry, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-5924; Fax: 416-813-5005; E-mail: deber{at}sickkids.ca.

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