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Originally published In Press as doi:10.1074/jbc.M108740200 on January 17, 2002

J. Biol. Chem., Vol. 277, Issue 15, 12879-12890, April 12, 2002
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The Ordered and Compartment-specific Autoproteolytic Removal of the Furin Intramolecular Chaperone Is Required for Enzyme Activation*

Eric D. AndersonDagger , Sean S. Molloy, François Jean§, Hao Fei, Satoko Shimamura, and Gary Thomas

From the Vollum Institute, Portland, Oregon 97201

The propeptide of furin has multiple roles in guiding the activation of the endoprotease in vivo. The 83-residue N-terminal propeptide is autoproteolytically excised in the endoplasmic reticulum (ER) at the consensus furin site, -Arg104-Thr-Lys-Arg107down-arrow -, but remains bound to furin as a potent autoinhibitor. Furin lacking the propeptide is ER-retained and proteolytically inactive. Co-expression with the propeptide, however, restores trans-Golgi network (TGN) localization and enzyme activity, indicating that the furin propeptide is an intramolecular chaperone. Blocking this step results in localization to the ER-Golgi intermediate compartment (ERGIC)/cis-Golgi network (CGN), suggesting the ER and ERGIC/CGN recognize distinct furin folding intermediates. Following transport to the acidified TGN/endosomal compartments, furin cleaves the bound propeptide at a second, internal P1/P6 Arg site (-Arg-Gly-Val72-Thr-Lys-Arg75down-arrow -) resulting in propeptide dissociation and enzyme activation. Cleavage at Arg75, however, is not required for proper furin trafficking. Kinetic analyses of peptide substrates indicate that the sequential pH-modulated propeptide cleavages result from the differential recognition of these sites by furin. Altering this preference by converting the internal site to a canonical P1/P4 Arg motif (Val72 right-arrow Arg) caused ER retention and blocked activation of furin, demonstrating that the structure of the furin propeptide mediates folding of the enzyme and directs its pH-regulated, compartment-specific activation in vivo.

* This work was supported by National Institutes of Health Grant DK37274.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Recipient of a Tartar Trust fellowship. Current address: Dept. of Cell Biology, Yale University School of Medicine, New Haven, CT 06510.

§ Recipient of a Medical Research Council (Canada) fellowship. Current address: Dept. of Microbiology, University of British Columbia, Vancouver, British Columbia VT6 1Z3, Canada.

To whom correspondence should be addressed. Tel.: 503-494-6955; Fax: 503-494-4534; E-mail: thomasg@ohsu.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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