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Glycobiology Advance Access published online on February 6, 2003
Glycobiology, doi:10.1093/glycob/cwg046
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Submitted on August 21, 2002
Revised on December 4, 2002
Accepted on January 7, 2003

© 2003 Oxford University Press

ORIGINAL ARTICLES

The binding of human glial cell line-derived neurotrophic factor (GDNF) to heparin and heparan sulphate: importance of 2-O-sulphate groups and effect on its interaction with its receptor GFR{alpha}1

Steven M. Rickard 1, Rosemary S. Mummery 1, Barbara Mulloy 2, Christopher C. Rider 1*

1 School of Biological Sciences, Royal Holloway University of London, Egham Hill, Egham, Surrey TW20 0EX, United Kingdom
2 Laboratory for Molecular Structure, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters bar, Hertfordshire, EN6 3QC, United Kingdom

* To whom correspondence should be addressed. E-mail: c.rider{at}rhul.ac.uk.

Abstract

We report ELISA studies of the glycosaminoglycan binding properties of recombinant human GDNF. We demonstrate relatively high affinity binding, as soluble heparin competes with an IC50 of 0.1 µg/ml. The binding of GDNF to heparin is particularly dependent on the presence of 2-O-sulphate groups. Highly sulphated heparan sulphate is also an effective competitor for GDNF binding. We further show that heparin at low concentrations protects GDNF from proteolytic modification by an endoprotease, and also promotes the binding of GDNF to its receptor polypeptide, GFR{alpha}1. In both these actions, 2-O-desulphated heparin is less effective. Taken overall, these findings provide strong support for a hypothesis that the bioactivity of GDNF during prenatal development is essentially dependent on the binding of this growth factor to 2-O-sulphate rich heparin-related glycosaminoglycan.


GDNF, GFR{alpha}1 receptor, glycosaminoglycan, heparan sulphate, heparin
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