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Published online
doi:10.1083/jcb.200703021
The Journal of Cell Biology, Vol. 178, No. 1, 167-178
The Rockefeller University Press, 0021-9525 $30.00
© Takahashi et al.
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Article

The RGD motif in fibronectin is essential for development but dispensable for fibril assembly



Seiichiro Takahashi1, Michael Leiss1, Markus Moser1, Tomoo Ohashi2, Tomoe Kitao3, Dominik Heckmann4, Alexander Pfeifer5, Horst Kessler4, Junichi Takagi3, Harold P. Erickson2, and Reinhard Fässler1

1 Max Planck Institute of Biochemistry, Department of Molecular Medicine, 82152 Martinsried, Germany
2 Department of Cell Biology, Duke University Medical Center, Durham, NC
3 Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Suita, Osaka, Japan
4 Center of Integrated Protein Science at Department Chemie, Technical University Munich, 85747 Garching, Germany
5 Institute of Pharmacology and Toxicology, University of Bonn, 53113 Bonn, Germany

Correspondence to Reinhard Fässler: faessler{at}biochem.mpg.de

Fibronectin (FN) is secreted as a disulfide-bonded FN dimer. Each subunit contains three types of repeating modules: FN-I, FN-II, and FN-III. The interactions of {alpha}5ß1 or {alpha}v integrins with the RGD motif of FN-III repeat 10 (FN-III10) are considered an essential step in the assembly of FN fibrils. To test this hypothesis in vivo, we replaced the RGD motif with the inactive RGE in mice. FN-RGE homozygous embryos die at embryonic day 10 with shortened posterior trunk, absent tail bud–derived somites, and severe vascular defects resembling the phenotype of {alpha}5 integrin–deficient mice. Surprisingly, the absence of a functional RGD motif in FN did not compromise assembly of an FN matrix in mutant embryos or on mutant cells. Matrix assembly assays and solid-phase binding assays reveal that {alpha}vß3 integrin assembles FN-RGE by binding an isoDGR motif in FN-I5, which is generated by the nonenzymatic rearrangement of asparagines (N) into an iso-aspartate (iso-D). Our findings demonstrate that FN contains a novel motif for integrin binding and fibril formation whose activity is controlled by amino acid modification.

S. Takahashi and M. Leiss contributed equally to this paper.

Abbreviations used in this paper: CS1, connecting segment-1; cycRAD, cyclo (-Arg-Ala-Asp-D-Phe-Val-) peptide; cycRGD, cyclo(-Arg-Gly-Asp-D-Phe-Val-) peptide; E, embryonic day; FN, fibronectin; isoDGR-2C, (*Cys-isoAsp-Gly-Arg-Cys*) peptide; linRGD, Gly-Arg-Gly-Asp-Ser-Pro peptide; linRGE, Gly-Arg-Gly-Glu-Ser-Pro peptide; LM111, laminin-111; NGR-2C, (*Cys-Asn-Gly-Arg-Cys*) peptide; VN, vitronectin.


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