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Originally published In Press as doi:10.1074/jbc.M210611200 on October 23, 2002

J. Biol. Chem., Vol. 277, Issue 52, 50795-50804, December 27, 2002
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Homo- and Heterotypic Fibrillin-1 and -2 Interactions Constitute the Basis for the Assembly of Microfibrils*

Guoqing LinDagger , Kerstin TiedemannDagger , Tillman VollbrandtDagger , Hannelore Peters§, Boris Bätge, Jürgen Brinckmann||, and Dieter P. ReinhardtDagger **

From the Departments of Dagger  Medical Molecular Biology, § Chemistry, and || Dermatology, University of Lübeck, D-23538 Lübeck and  Klinikum Neustadt, D-23730 Neustadt, Germany

Fibrillin-1 and fibrillin-2 constitute the backbone of extracellular filaments, called microfibrils. Fibrillin assembly involves complex multistep mechanisms to result in a periodical head-to-tail alignment in microfibrils. Impaired assembly potentially plays a role in the molecular pathogenesis of genetic disorders caused by mutations in fibrillin-1 (Marfan syndrome) and fibrillin-2 (congenital contractural arachnodactyly). Presently, the basic molecular interactions involved in fibrillin assembly are obscure. Here, we have generated recombinant full-length human fibrillin-1, and two overlapping recombinant polypeptides spanning the entire human fibrillin-2 in a mammalian expression system. Characterization by gel electrophoresis, electron microscopy after rotary shadowing, and reactivity with antibodies demonstrated correct folding of these recombinant polypeptides. Analyses of homotypic and heterotypic interaction repertoires showed N- to C-terminal binding of fibrillin-1, and of fibrillin-1 with fibrillin-2. The interactions were of high affinity with dissociation constants in the low nanomolar range. However, the N- and C-terminal fibrillin-2 polypeptides did not interact with each other. These results demonstrate that fibrillins can directly interact in an N- to C-terminal fashion to form homotypic fibrillin-1 or heterotypic fibrillin-1/fibrillin-2 microfibrils. This conclusion was further strengthened by double immunofluorescence labeling of microfibrils. In addition, the binding epitopes as well as the entire fibrillin molecules displayed very stable properties.

* This work was supported by Deutsche Forschungsgemeinschaft Grants SFB367-A1, RE1021/3-2, and RE1021/4-2.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Dept. of Medical Molecular Biology, University of Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. Tel.: 49-451-500-4086; Fax: 49-451-500-3637; E-mail: reinhardt@molbio.mu-luebeck.de.

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