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Vol. 16, Issue 11, 5215-5226, November 2005

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The Cysteine-rich Domain of the Secreted Proprotein Convertases PC5A and PACE4 Functions as a Cell Surface Anchor and Interacts with Tissue Inhibitors of Metalloproteinases

Nadia Nour , Gaétan Mayer ^* , John S. Mort , Alexandre Salvas ^*, Majambu Mbikay , Charlotte J. Morrison ^||, Christopher M. Overall ^||, and Nabil G. Seidah ^*

^* Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada; Joint Diseases Laboratory, Shriners Hospitals for Children, Montreal, Quebec H3G 1A6, Canada; Diseases of Aging Program, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario K1Y 4K9, Canada; and ^|| Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

Submitted June 8, 2005; Revised August 5, 2005; Accepted August 23, 2005
Monitoring Editor: Guido Guidotti

The proprotein convertases PC5, PACE4 and furin contain a C-terminal cysteine-rich domain (CRD) of unknown function. We demonstrate that the CRD confers to PC5A and PACE4 properties to bind tissue inhibitors of metalloproteinases (TIMPs) and the cell surface. Confocal microscopy and biochemical analyses revealed that the CRD is essential for cell surface tethering of PC5A and PACE4 and that it colocalizes and coimmunoprecipitates with the full-length and C-terminal domain of TIMP-2. Surface-bound PC5A in TIMP-2 null fibroblasts was only observed upon coexpression with TIMP-2. In COS-1 cells, plasma membrane-associated PC5A can be displaced by heparin, suramin, or heparinases I and III and by competition with excess exogenous TIMP-2. Furthermore, PC5A and TIMP-2 are shown to be colocalized over the surface of enterocytes in the mouse duodenum and jejunum, as well as in liver sinusoids. In conclusion, the CRD of PC5A and PACE4 functions as a cell surface anchor favoring the processing of their cognate surface-anchored substrates, including endothelial lipase.

Abbreviations used: aa, amino acid; Ab, antibody; ConA, concanavalin A; CRD, cysteine-rich domain; EL, endothelial lipase; ECM, extracellular matrix FBS; HSPG, heparan sulfate proteoglycan; MMP, matrix metalloproteinase; PC, proprotein convertase; TIMP-2-LP, TIMP-2-Lamp1 protein; TIMP, tissue inhibitor of metalloproteinase; TM-CT, transmembrane-cytosolic tail; WT, wild type; NT-, N-terminal; CT-, C-terminal.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

Address correspondence to: Nabil G. Seidah (seidahn{at}ircm.qc.ca).

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