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Glycobiology Advance Access originally published online on February 6, 2003
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Glycobiology, 2003, Vol. 13, No. 6 419-426
© 2003 Oxford University Press

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

Steven M. Rickard1,3, Rosemary S. Mummery3, Barbara Mulloy4 and Christopher C. Rider2,3

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

Received on August 21, 2002; revised on December 4, 2002; accepted on January 7, 2003

We report ELISA studies of the glycosaminoglycan binding properties of recombinant human glial cell line–derived neurotrophic factor (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-sulfate groups. Highly sulfated heparan sulfate is also an effective competitor for GDNF binding. We also 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 of these actions, 2-O-desulfated heparin is less effective. Considered 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-sulfate-rich heparin-related glycosaminoglycan.

1 Present address: Department of Ocular Immunology, Institute of Ophthalmology, Bath Street, London, EC1V 9EL, United Kingdom

2 To whom correspondence should be addressed; e-mail: c.rider{at}rhul.ac.uk


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