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M300394200v1
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Papers In Press, published online ahead of print May 5, 2003
J. Biol. Chem, 10.1074/jbc.M300394200
Submitted on January 14, 2003
Revised on May 5, 2003
Accepted on May 5, 2003

Prion or amyloid-b-derived Cu(II)- 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

Department of Cell and Molecular Biology, Lund University, Lund S-221 84

Corresponding Author: Lars-Ake.Fransson{at}medkem.lu.se

Copper-ions are generally bound to proteins, e.g. the prion and the amyloid beta 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 step-wise manner while 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, while they inhibit copper(II)-supported degradation, and (d) copper(II)-loaded, but not zinc(II)-loaded, prion protein or amyloid beta 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.


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