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Vol. 20, Issue 3, 846-858, February 1, 2009

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Fibrillin Assembly Requires Fibronectin

Laetitia Sabatier^*,, Daliang Chen^*,, Christine Fagotto-Kaufmann^*, Dirk Hubmacher^*, Marc D. McKee^*,, Douglas S. Annis, Deane F. Mosher, and Dieter P. Reinhardt^*,

*Faculty of Medicine, Department of Anatomy and Cell Biology, and Faculty of Dentistry, McGill University, Montreal, QC, Canada H3A 2B2; and Departments of Biomolecular Chemistry and Medicine, University of Wisconsin, Madison, WI 53706

Submitted August 13, 2008; Revised October 27, 2008; Accepted November 17, 2008
Monitoring Editor: Jean E. Schwarzbauer

InCytes from MBC

Fibrillins constitute the major backbone of multifunctional microfibrils in elastic and nonelastic extracellular matrices. Proper assembly mechanisms are central to the formation and function of these microfibrils, and their properties are often compromised in pathological circumstances such as in Marfan syndrome and in other fibrillinopathies. Here, we have used human dermal fibroblasts to analyze the assembly of fibrillin-1 in dependence of other matrix-forming proteins. siRNA knockdown experiments demonstrated that the assembly of fibrillin-1 is strictly dependent on the presence of extracellular fibronectin fibrils. Immunolabeling performed at the light and electron microscopic level showed colocalization of fibrillin-1 with fibronectin fibrils at the early stages of the assembly process. Protein-binding assays demonstrated interactions of fibronectin with a C-terminal region of fibrillin-1, -2, and -3 and with an N-terminal region of fibrillin-1. The C-terminal half of fibrillin-2 and -3 had propensities to multimerize, as has been previously shown for fibrillin-1. The C-terminal of all three fibrillins interacted strongly with fibronectin as multimers, but not as monomers. Mapping studies revealed that the major binding interaction between fibrillins and fibronectin involves the collagen/gelatin-binding region between domains FNI₆ and FNI₉.

These authors contributed equally to this work.

Address correspondence to: Dieter Reinhardt (dieter.reinhardt{at}mcgill.ca)

Abbreviations used: DTT, dithiothreitol; HSF, human skin fibroblasts; LTBP, latent transforming growth factor—binding protein; PBS, phosphate-buffered saline; TBS, Tris-buffered saline; TGF-β, transforming growth factor-β.

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