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J. Biol. Chem., Vol. 283, Issue 40, 27017-27027, October 3, 2008

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Heparan Sulfate Regulates Fibrillin-1 N- and C-terminal Interactions^*

Stuart A. Cain¹, Andrew K. Baldwin¹, Yashithra Mahalingam¹², Bertrand Raynal^¶, Thomas A. Jowitt, C. Adrian Shuttleworth, John R. Couchman^||23, and Cay M. Kielty, A Royal Society Wolfson Research Merit Award holder⁴

From the Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, United Kingdom, the Division of Biomedical Sciences, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom, ^||Biomedicine Institute, University of Copenhagen, Biocenter, Ole Maoløes Vej 5, 2200 Copenhagen, Denmark, and ^¶Plate-Forme de Biophysique de Macromolécules et de Leurs Interactions, Institut Pasteur 25, Rue du Docteur Roux, 75724 Paris Cedex 15, France

Fibrillin-1 N- and C-terminal heparin binding sites have been characterized. An unprocessed monomeric N-terminal fragment (PF1) induced a very high heparin binding response, indicating heparin-mediated multimerization. Using PF1 deletion and short fragments, a heparin binding site was localized within the domain encoded by exon 7 after the first hybrid domain. Rodent embryonic fibroblasts adhered to PF1 and deletion fragments, and, when cells were plated on fibrillin-1 or fibronectin Arg-Gly-Asp cell-binding fragments, cells showed heparin-dependent spreading and focal contact formation in response to soluble PF1. Within domains encoded by exons 59–62 near the fibrillin-1 C terminus are novel conformation-dependent high affinity heparin and tropoelastin binding sites. Heparin disrupted tropoelastin binding but did not disrupt N- and C-terminal fibrillin-1 interactions. Thus, fibrillin-1 N-terminal interactions with heparin/heparan sulfate directly influence cell behavior, whereas C-terminal interactions with heparin/heparan sulfate regulate elastin deposition. These data highlight how heparin/heparan sulfate controls fibrillin-1 interactions.

Received for publication, May 2, 2008 , and in revised form, July 28, 2008.

^* This work was funded by British Heart Foundation Grant PG/04/052/17027, Wellcome Trust Grant 081930, Medical Research Council Grant G0200246, and European Union Grant LSHM-CT-2005-018960. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ These authors contributed equally to this work.

² Supported by Wellcome Trust Grant 065940.

³ Supported by the Danish National Research Foundation.

⁴ To whom correspondence should be addressed: Faculty of Life Sciences, University of Manchester, Michael Smith Bldg., Oxford Road, Manchester, M13 9PT, United Kingdom. Tel.: 44-161-275-5739; Fax: 44-161-275-5082; E-mail: cay.kielty{at}manchester.ac.uk.

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