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Originally published In Press as doi:10.1074/jbc.M203404200 on June 10, 2002

J. Biol. Chem., Vol. 277, Issue 34, 30567-30573, August 23, 2002
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Biosynthetic Oligosaccharide Libraries for Identification of Protein-binding Heparan Sulfate Motifs
EXPLORING THE STRUCTURAL DIVERSITY BY SCREENING FOR FIBROBLAST GROWTH FACTOR (FGF) 1 AND FGF2 BINDING*

Per JemthDagger , Johan KreugerDagger , Marion Kusche-GullbergDagger , Luisa Sturiale§, Guillermo Giménez-Gallego||, and Ulf LindahlDagger **

From the Dagger  Department of Medical Biochemistry and Microbiology, Uppsala University, Biomedical Center, Box 582, SE-751 23 Uppsala, Sweden, § G. Ronzoni Institute for Chemical and Biochemical Research, via G. Colombo, 81-20133 Milan, Italy, and || Centro de Investigaciones Biológicas (Consejo Superior de Investigaciones Científicas), Velázques, 144, 28006 Madrid, Spain

Heparan sulfate is crucial for vital reactions in the body because of its ability to bind various proteins. The identification of protein-binding heparan sulfate sequences is essential to our understanding of heparan sulfate biology and raises the possibility to develop drugs against diseases such as cancer and inflammatory conditions. We present proof-of-principle that in vitro generated heparan sulfate oligosaccharide libraries can be used to explore interactions between heparan sulfate and proteins, and that the libraries expand the available heparan sulfate sequence space. Oligosaccharide libraries mimicking highly 6-O-sulfated domains of heparan sulfate were constructed by enzymatic O-sulfation of O-desulfated, end-group 3H-labeled heparin octasaccharides. Acceptor oligosaccharides that were 6-O-desulfated but only partially 2-O-desulfated yielded oligosaccharide arrays with increased ratio of iduronyl 2-O-sulfate/glucosaminyl 6-O-sulfate. The products were probed by affinity chromatography on immobilized growth factors, fibroblast growth factor-1 (FGF1) and FGF2, followed by sequence analysis of trapped oligosaccharides. An N-sulfated octasaccharide, devoid of 2-O-sulfate but with three 6-O-sulfate groups, was unexpectedly found to bind FGF1 as well as FGF2 at physiological ionic strength. However, a single 2-O-sulfate group in the absence of 6-O-sulfation gave higher affinity for FGF2. FGF1 binding was also augmented by 2-O-sulfation, preferentially in combination with an adjacent upstream 6-O-sulfate group. These results demonstrate the potential of the enzymatically generated oligosaccharide libraries.

* This work was supported by European Commission Grants QLK-CT-1999.00536 (Program "Biologically Active Novel Glycosaminoglycans") and BIO4-CT98-0538 (Program "Heparan Sulfate Sequencing Demonstration"), by Swedish Research Council Grant 13401, and by a grant from Polysackaridforskning AB. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Istituto per la Chimica e la Tecnologia dei Materiali Polimerici, Consiglio Nazionale delle Ricerche, 6-95125 Catania, Italy.

** To whom correspondence should be addressed. Tel.: 46-18-471-4196; Fax: 46-18-471-4209; E-mail: ulf.lindahl@imbim.uu.se.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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