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J. Biol. Chem., Vol. 282, Issue 2, 1136-1143, January 12, 2007

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A Hydrophobic Patch in a Charged -Helix Is Sufficient to Target Proteins to Dense Core Secretory Granules^*

From the Laboratory of Molecular Biochemistry of Hypertension, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada

Many endocrine and neuroendocrine cells contain specialized secretory organelles called dense core secretory granules. These organelles are the repository of proteins and peptides that are secreted in a regulated manner when the cell receives a physiological stimulus. The targeting of proteins to these secretory granules is crucial for the generation of certain peptide hormones, including insulin and ACTH. Although previous work has demonstrated that proteins destined to a variety of cellular locations, including secretory granules, contain targeting sequences, no single consensus sequence for secretory granule-sorting signals has emerged. We have shown previously that -helical domains in the C-terminal tail of the prohormone convertase PC1/3 play an important role in the ability of this region of the protein to direct secretory granule targeting (Jutras, I. Seidah, N. G., and Reudelhuber, T. L. (2000) J. Biol. Chem. 275, 40337–40343). In this study, we show that a variety of -helical domains are capable of directing a heterologous secretory protein to granules. By testing a series of synthetic -helices, we also demonstrate that the presence of charged (either positive or negative) amino acids spatially segregated from a hydrophobic patch in the -helices of secretory proteins likely plays a critical role in the ability of these structures to direct secretory granule sorting.

Received for publication, June 14, 2006 , and in revised form, November 8, 2006.

^{* *} This work was supported by Canadian Institutes of Health Research Operating Grant MOP-53177 (to T. L. R.). 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: IRCM, 110, Avenue des Pins Ouest, Montreal, Quebec H2W 1R7, Canada. Tel.: 514-987-5716; Fax: 514-987-5717; E-mail: reudelt{at}ircm.qc.ca.

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