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J. Biol. Chem., Vol. 277, Issue 21, 18421-18430, May 24, 2002
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From the Data from cell culture and animal models of prion
disease support the separate involvement of both heparan sulfate
proteoglycans and copper (II) ions in prion (PrP) metabolism. Though
direct interactions between prion protein and heparin have been
recorded, little is known of the structural features implicit in this
interaction or of the involvement of copper (II) ions. Using biosensor
and enzyme-linked immunosorbent assay methodology we report direct heparin and heparan sulfate-binding activity in recombinant cellular prion protein (PrPc). We also demonstrate that the
interaction of recombinant PrPc with heparin is weakened in
the presence of Cu(II) ions and is particularly sensitive to
competition with dextran sulfate. Competitive inhibition experiments
with chemically modified heparins also indicate that
2-O-sulfate groups (but not 6-O-sulfate groups) are essential for heparin recognition. We have also identified three
regions of the prion protein capable of independent binding to heparin
and heparan sulfate: residues 23-52, 53-93, and 110-128. Interestingly, the interaction of an octapeptide-spanning peptide motif
amino acids 53-93 with heparin is enhanced by Cu(II) ions. Significantly, a peptide of this sequence is able to inhibit the binding of full-length prion molecule to heparin, suggesting a direct
role in heparin recognition within the intact protein. The collective
data suggest a complex interaction between prion protein and
heparin/heparan sulfate and has implications for the cellular and
pathological functions of prion proteins.
Identification of the Heparan Sulfate Binding Sites in the
Cellular Prion Protein*
,
Molecular Cell Biology Laboratories, School
of Biosciences, University of Birmingham, Edgbaston, Birmingham,
England B15 2TT, United Kingdom and the § Laboratorium
für Molekulare Biologie-Genzentrum-Institut für Biochemie,
der LMU, Feodor-Lynen-Strasse 25, Munich D-81377, Germany
*
This work was supported in part by Grants BIOMED PL976054
and QLRT-2000-02085 from the European Union.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.
Recipient of a Medical Research Council (UK) Senior Research
Fellowship. To whom correspondence should be addressed: Tel.: 44-0-121-414-7527; Fax: 44-0-870-121-0564; E-mail:
j.e.turnbull@bham.ac.uk.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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