Fibronectin (FN) is an essential glycoprotein of the extracellular matrix; binds integrins, syndecans, collagens, and growth factors; and is assembled by cells into complex fibrillar networks. The RGD motif in FN facilitates cell binding and fibrillogenesis through binding to α5β1 and αv-class integrins. However, whether RGD is the sole binding site for αv-class integrins is unclear. Most notably, substituting aspartate with glutamate (RGE) was shown to eliminate integrin binding in vitro, while mouse genetics revealed that FNRGE preserves αv-class integrin binding and fibrillogenesis. To address this conflict, we employed single-cell force spectroscopy, engineered cells, and RGD motif–deficient mice (Fn1ΔRGD/ΔRGD) to search for additional αv-class integrin–binding sites. Our results demonstrate that α5β1 and αv-class integrins solely recognize the FN-RGD motif and that αv-class, but not α5β1, integrins retain FN-RGE binding. Furthermore, Fn1ΔRGD/ΔRGD tissues and cells assemble abnormal and dysfunctional FNΔRGD fibrils in a syndecan-dependent manner. Our data highlight the central role of FN-RGD and the functionality of FN-RGE for αv-class integrins.
αv-Class integrin binding to fibronectin is solely mediated by RGD and unaffected by an RGE mutation
M. Moser’s present address is Center for Translational Cancer Research, TUM School of Medicine, Technische Universität München, Munich, Germany.
M. Benito-Jardón’s present address is Francis Crick Institute, London, UK.
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María Benito-Jardón, Nico Strohmeyer, Sheila Ortega-Sanchís, Mitasha Bharadwaj, Markus Moser, Daniel J. Müller, Reinhard Fässler, Mercedes Costell; αv-Class integrin binding to fibronectin is solely mediated by RGD and unaffected by an RGE mutation. J Cell Biol 7 December 2020; 219 (12): e202004198. doi: https://doi.org/10.1083/jcb.202004198
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