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J. Biol. Chem., Vol. 282, Issue 32, 23362-23371, August 10, 2007

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Trafficking of a Secretory Granule Membrane Protein Is Sensitive to Copper^*

Mithu De, Giuseppe D. Ciccotosto, Richard E. Mains, and Betty A. Eipper¹

From the University of Connecticut Health Center, Farmington, Connecticut 06030-3401 and the University of Melbourne, Victoria 3010, Australia

We explored the effect of copper availability on the synthesis and trafficking of peptidylglycine -amidating monooxygenase (PAM), an essential cuproenzyme whose catalytic domains function in the lumen of peptide-containing secretory granules. Corticotrope tumor cell lines expressing integral membrane and soluble forms of PAM were depleted of copper using bathocuproinedisulfonic acid or loaded with copper by incubation with CuCl₂. Depleting cellular copper stimulates basal secretion of soluble enzyme produced by endoproteolytic cleavage of PAM in secretory granules and transit of membrane PAM though the endocytic pathway and back into secretory granules. Unlike many cuproenzymes, lack of copper does not lead to instability of PAM. Copper loading decreases cleavage of PAM in secretory granules, secretion of soluble enzyme, and the return of internalized PAM to secretory granules. The trafficking and stability of the soluble, luminal domain of PAM and truncated membrane PAM lacking a cytosolic domain are not affected by copper availability. Taken together, our data demonstrate a role for copper-sensitive cytosolic machinery in directing endocytosed membrane PAM back to secretory granules or to a degradative pathway. The response of PAM to lack of copper suggests that it facilitates copper homeostasis.

Received for publication, April 5, 2007 , and in revised form, May 7, 2007.

^* This work was supported by National Institutes of Health Grant DK-32949 (to B. A. E. and R. E. M.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ To whom correspondence should be addressed: 263 Farmington Ave., Farmington, CT 06030-3401. E-mail: eipper{at}uchc.edu.

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