Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes

Raphael Reuten, Trushar R. Patel, Matthew McDougall, Nicolas Rama, Denise Nikodemus, Benjamin Gibert, Jean-Guy Delcros, Carina Prein, Markus Meier, Stéphanie Metzger, Zhigang Zhou, Jennifer Kaltenberg, Karen K. McKee, Tobias Bald, Thomas Tüting, Paola Zigrino, Valentin Djonov, Wilhelm Bloch, Hauke Clausen-Schaumann, Ernst Poschl, Peter D. Yurchenco, Martin Ehrbar, Patrick Mehlen (), Jörg Stetefeld () and Manuel Koch ()
Additional contact information
Raphael Reuten: Institute for Dental Research and Oral Musculoskeletal Biology, Medical Faculty, University of Cologne
Trushar R. Patel: Alberta RNA Research and Training Institute, University of Lethbridge
Matthew McDougall: University of Manitoba
Nicolas Rama: Apoptosis, Cancer and Development Laboratory, Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon
Denise Nikodemus: Institute for Dental Research and Oral Musculoskeletal Biology, Medical Faculty, University of Cologne
Benjamin Gibert: Apoptosis, Cancer and Development Laboratory, Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon
Jean-Guy Delcros: Apoptosis, Cancer and Development Laboratory, Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon
Carina Prein: Center for Applied Tissue Engineering and Regenerative Medicine–CANTER, Munich University of Applied Sciences
Markus Meier: University of Manitoba
Stéphanie Metzger: Laboratory for Cell and Tissue Engineering, University Hospital Zurich
Zhigang Zhou: School of Biological Sciences, University of East Anglia, Norwich Research Park
Jennifer Kaltenberg: Institute for Dental Research and Oral Musculoskeletal Biology, Medical Faculty, University of Cologne
Karen K. McKee: Robert Wood Johnson Medical School
Tobias Bald: University Hospital Magdeburg
Thomas Tüting: University Hospital Magdeburg
Paola Zigrino: University of Cologne
Valentin Djonov: Institute of Anatomy, University of Bern
Wilhelm Bloch: Institute of Cardiovascular Research and Sport Medicine, German Sport University Cologne
Hauke Clausen-Schaumann: Center for Applied Tissue Engineering and Regenerative Medicine–CANTER, Munich University of Applied Sciences
Ernst Poschl: School of Biological Sciences, University of East Anglia, Norwich Research Park
Peter D. Yurchenco: Robert Wood Johnson Medical School
Martin Ehrbar: Laboratory for Cell and Tissue Engineering, University Hospital Zurich
Patrick Mehlen: Apoptosis, Cancer and Development Laboratory, Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon
Jörg Stetefeld: University of Manitoba
Manuel Koch: Institute for Dental Research and Oral Musculoskeletal Biology, Medical Faculty, University of Cologne

Nature Communications, 2016, vol. 7, issue 1, 1-17

Abstract: Abstract Netrins, a family of laminin-related molecules, have been proposed to act as guidance cues either during nervous system development or the establishment of the vascular system. This was clearly demonstrated for netrin-1 via its interaction with the receptors DCC and UNC5s. However, mainly based on shared homologies with netrin-1, netrin-4 was also proposed to play a role in neuronal outgrowth and developmental/pathological angiogenesis via interactions with netrin-1 receptors. Here, we present the high-resolution structure of netrin-4, which shows unique features in comparison with netrin-1, and show that it does not bind directly to any of the known netrin-1 receptors. We show that netrin-4 disrupts laminin networks and basement membranes (BMs) through high-affinity binding to the laminin γ1 chain. We hypothesize that this laminin-related function is essential for the previously described effects on axon growth promotion and angiogenesis. Our study unveils netrin-4 as a non-enzymatic extracellular matrix protein actively disrupting pre-existing BMs.

Date: 2016
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DOI: 10.1038/ncomms13515

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