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J. Biol. Chem., Vol. 280, Issue 12, 11404-11412, March 25, 2005

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Microfibrils at Basement Membrane Zones Interact with Perlecan via Fibrillin-1^*

Kerstin Tiedemann, Takako Sasaki, Erika Gustafsson¶, Walter Göhring, Boris Bätge||, Holger Notbohm, Rupert Timpl, Thilo Wedel**, Ursula Schlötzer-Schrehardt, and Dieter P. Reinhardt¶¶

From the Department of Medical Molecular Biology, University of Lübeck, 23538 Lübeck, Germany, the Department of Protein Chemistry, Max-Planck-Institute for Biochemistry, 82152 Martinsried, Germany, the ^¶Department of Experimental Pathology, Lund University, 22185 Lund, Sweden, ^||Klinikum Neustadt, 23730 Neustadt, Germany, the ^**Department of Anatomy, University of Lübeck, 23538 Lübeck, Germany, the Department of Ophthalmology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany, and Faculty of Medicine, Department of Anatomy and Cell Biology, and Faculty of Dentistry, McGill University, Montreal, Quebec H3A 2B2, Canada

Mutational defects in fibrillin-rich microfibrils give rise to a number of heritable connective tissue disorders, generally termed microfibrillopathies. To understand the pathogenesis of these microfibrillopathies, it is important to elucidate the supramolecular composition of microfibrils and their interaction properties with extracellular matrix components. Here we demonstrate that the proteoglycan perlecan is an associated component of microfibrils typically close to basement membrane zones. Double immunofluorescence studies demonstrate colocalization of fibrillin-1, the major backbone component of microfibrils, with perlecan in fibroblast cultures as well as in dermal and ocular tissues. Double immunogold labeling further confirms colocalization of perlecan to microfibrils in various tissues at the ultrastructural level. Extraction studies revealed that perlecan is not covalently associated with microfibrils. High affinity interactions between fibrillin-1 and perlecan were found by kinetic binding studies with dissociation constants in the low nanomolar range. A detailed mapping study of the interaction epitopes by solid phase binding assays primarily revealed interactions of perlecan domains I and II with a central region of fibrillin-1. Analysis of perlecan null embryos showed less microfibrils at the dermal-epidermal junction as compared with wild-type littermates. The data presented indicate a functional significance for perlecan in anchoring microfibrils to basement membranes and in the biogenesis of microfibrils.

Received for publication, August 27, 2004 , and in revised form, December 17, 2004.

^* This work was supported by the Deutsche Forschungsgemeinschaft Grants Re1021/4-2 and SFB367-A1 and the Canadian Institutes of Health Research Grant MOP-68836. 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.

Deceased October, 2003.

^¶¶ To whom correspondence should be addressed: Faculty of Medicine, Dept. of Anatomy and Cell Biology, and Faculty of Dentistry, McGill University, 3640 University St., Montreal, Quebec H3A 2B2, Canada. Tel.: 1-514-398-4243; Fax: 1-514-398-4020; E-mail: dieter.reinhardt{at}mcgill.ca.

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