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J. Biol. Chem., Vol. 278, Issue 40, 38956-38965, October 3, 2003

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Prion, Amyloid -derived Cu(II) Ions, or Free Zn(II) Ions Support S-Nitroso-dependent Autocleavage of Glypican-1 Heparan Sulfate^*

Katrin Mani, Fang Cheng, Birgitta Havsmark, Mats Jönsson, Mattias Belting  and Lars-Åke Fransson 

From the Department of Cell and Molecular Biology, Section for Cell and Matrix Biology, Lund University, BMC C13, SE-221 84 Lund, Sweden

Copper are generally bound to proteins, e.g. the prion and the amyloid proteins. We have previously shown that copper ions are required to nitrosylate thiol groups in the core protein of glypican-1, a heparan sulfate-substituted proteoglycan. When S-nitrosylated glypican-1 is then exposed to an appropriate reducing agent, such as ascorbate, nitric oxide is released and autocatalyzes deaminative cleavage of the glypican-1 heparan sulfate side chains at sites where the glucosamines are N-unsubstituted. These processes take place in a stepwise manner, whereas glypican-1 recycles via a caveolin-1-associated pathway where copper ions could be provided by the prion protein. Here we show, by using both biochemical and microscopic techniques, that (a) the glypican-1 core protein binds copper(II) ions, reduces them to copper(I) when the thiols are nitrosylated and reoxidizes copper(I) to copper(II) when ascorbate releases nitric oxide; (b) maximally S-nitrosylated glypican-1 can cleave its own heparan sulfate chains at all available sites in a nitroxyl ion-dependent reaction; (c) free zinc(II) ions, which are redox inert, also support autocleavage of glypican-1 heparan sulfate, probably via transnitrosation, whereas they inhibit copper(II)-supported degradation; and (d) copper(II)-loaded but not zinc(II)-loaded prion protein or amyloid peptide support heparan sulfate degradation. As glypican-1 in prion null cells is poorly S-nitrosylated and as ectopic expression of cellular prion protein restores S-nitrosylation of glypican-1 in these cells, we propose that one function of the cellular prion protein is to deliver copper(II) for the S-nitrosylation of recycling glypican-1.

Received for publication, January 14, 2003 , and in revised form, May 5, 2003.

^* The work was supported grants from the Swedish Science Council (VR-M), the Cancer Fund, the Strategic Research Fund ("Glycoconjugates in Biological Systems" to F. C.), the Tegger, Kock and Österlund Foundations, Xylogen AB, Polysackaridforskning i Uppsala AB, and the Medical Faculty of Lund University. 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.

Present address: Depts. of Immunology and Vascular Biology, The Scripps Research Institute, C-204, 10550 N. Torrey Pines Rd., La Jolla, CA 92014.

To whom correspondence should be addressed. Tel.: 46-46-222-8573; Fax: 46-46-222-3128; E-mail: lars-ake.fransson{at}medkem.lu.se.

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