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J. Biol. Chem., Vol. 281, Issue 41, 30492-30502, October 13, 2006

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The Translocation Inhibitor CAM741 Interferes with Vascular Cell Adhesion Molecule 1 Signal Peptide Insertion at the Translocon^*

From the Novartis Institutes for BioMedical Research, A-1235 Vienna, Austria

The cyclopeptolide CAM741 selectively inhibits cotranslational translocation of vascular cell adhesion molecule 1 (VCAM1), a process that is dependent on its signal peptide. In this study we identified the C-terminal (C-) region upstream of the cleavage site of the VCAM1 signal peptide as most critical for inhibition of translocation by CAM741, but full sensitivity to the compound also requires residues of the hydrophobic (h-) region and the first amino acid of the VCAM1 mature domain. The murine VCAM1 signal peptide, which is less susceptible to translocation inhibition by CAM741, can be converted into a fully sensitive signal peptide by two amino acid substitutions identified as critical for compound sensitivity of the human VCAM1 signal peptide. Using cysteine substitutions of non-critical residues in the human VCAM1 signal peptide and chemical cross-linking of targeted short nascent chains we show that, in the presence of CAM741, the N- and C-terminal segments of the VCAM1 signal peptide could be cross-linked to the cytoplasmic tail of Sec61, indicating altered positioning of the VCAM1 signal peptide relative to this translocon component. Moreover, translocation of a tag fused N-terminal to the VCAM1 signal peptide is selectively inhibited by CAM741. Our data indicate that the compound inhibits translocation of VCAM1 by interfering with correct insertion of its signal peptide into the translocon.

Received for publication, July 31, 2006

^* 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 To whom correspondence should be addressed: Novartis Institutes for Biomedical Research, Brunner Strasse 59, A-1235 Vienna, Austria. Tel.: 43-1-86634-330; Fax: 43-1-86634-727; E-mail: Hanna.Harant{at}novartis.com.

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				H. Harant, B. Wolff, E. P. Schreiner, B. Oberhauser, L. Hofer, N. Lettner, S. Maier, J. E. de Vries, and I. J. Lindley Inhibition of Vascular Endothelial Growth Factor Cotranslational Translocation by the Cyclopeptolide CAM741 Mol. Pharmacol., June 1, 2007; 71(6): 1657 - 1665. [Abstract] [Full Text] [PDF]