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J. Biol. Chem., Vol. 276, Issue 20, 16711-16719, May 18, 2001
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From the The prion protein is known to be a copper-binding
protein, but affinity and stoichiometry data for the full-length
protein at a physiological pH of 7 were lacking. Furthermore, it was
unknown whether only the highly flexible N-terminal segment with its
octarepeat region is involved in copper binding or whether the
structured C-terminal domain is also involved. Therefore we
systematically investigated the stoichiometry and affinity of copper
binding to full-length prion protein PrP23-231 and
to different N- and C-terminal fragments using electrospray ionization
mass spectrometry and fluorescence spectroscopy. Our data indicate that
the unstructured N-terminal segment is the cooperative copper-binding domain of the prion protein. The prion protein binds up to five copper(II) ions with half-maximal binding at ~2 µM.
This argues strongly for a direct role of the prion protein in copper
metabolism, since it is almost saturated at about 5 µM,
and the exchangeable copper pool concentration in blood is about 8 µM.
Prion Protein Binds Copper within the Physiological Concentration
Range*
§,
,,**,,**
Department of Neuropathology, Georg August
University of Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany, the ¶ Department of Immunochemistry,
Max-Planck Institute for Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Göttingen, Germany, the Department of Biochemistry
II, Georg August University of Göttingen,
Heinrich-Düker-Weg 12, 37073 Göttingen, Germany, the
Laboratory of Molecular Medicine,
Children's Hospital, Boston, Massachusetts 02115, and the
§§ Institute of Molecular Virology,
GSF-Center for Environmental and Health Research, Technical
University of Munich, Trogerstrasse
4b, 81675 München, Germany
*
This work was supported by the European Union Grant
BMH4-CT98-6051, by the BMBF of Germany, and by a grant from the
Boehringer Ingelheim Fonds (to S. H.).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.
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