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J. Biol. Chem., Vol. 279, Issue 22, 23142-23150, May 28, 2004

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Spacrcan Binding to Hyaluronan and Other Glycosaminoglycans

MOLECULAR AND BIOCHEMICAL STUDIES^*

Qiuyun Chen¶, Shenshen Cai||, Karen G. Shadrach, Glenn D. Prestwich||, and Joe G. Hollyfield

From the Cole Eye Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195 and the ^||Department of Medicinal Chemistry, The University of Utah, Salt Lake City, Utah 84108-1257

Photoreceptors project from the outer retinal surface into a specialized glycocalyx, the interphotoreceptor matrix (IPM), which contains hyaluronan (HA) and two novel proteoglycans, Spacr and Spacrcan. This matrix must be stable enough to function in the attachment of the retina to the outer eye wall yet porous enough to allow movement of metabolites between these tissues. How this matrix is organized is not known. HA is a potential candidate in IPM organization since biochemical studies show that these proteoglycans bind HA. RHAMM (receptor for HA-mediated motility)-type HA binding motifs (HABMs) are present in their deduced amino acid sequence and may be the sites of this HA interaction. To test this hypothesis, we subcloned three fragments of mouse Spacrcan that contain the putative HABMs. We found that each recombinant fragment binds HA. Binding decreased when residues in the HABMs were mutated. This provides direct evidence that the RHAMM-type HABMs in Spacrcan are involved in hyaluronan binding. Since chondroitin sulfate and heparan sulfate proteoglycans are important for retinal development and function, we also evaluated the binding of these recombinant proteins to heparin and chondroitin sulfates, the glycosaminoglycan side chain of these proteoglycans. We found that each recombinant protein bound to both heparin and chondroitin sulfates. Binding to chondroitin sulfates involved these HABMs, because mutagenesis reduced binding. Binding to heparin was probably not mediated through these HABMs since heparin binding persisted following their mutagenesis. These studies provide the first evidence defining the sites of protein-carbohydrate interaction of molecules present in the IPM.

Received for publication, February 12, 2004 , and in revised form, March 25, 2004.

^* This work was supported by Grants EY02362 (to J. G. H.), R43 CA81820 (to Jodie L. Dufner-Beattie), and DC 04336 (to G. D. P. and the late Steven D. Gray) from the National Institutes of Health. 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.

Both authors contributed equally to this work.

^¶ To whom correspondence should be addressed. Tel.: 216-445-1933; Fax: 216-445-3670; E-mail: chenq2{at}ccf.org.

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