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 PoschlPeter D. Yurchenco, Martin Ehrbar, Patrick Mehlen, Jörg Stetefeld, Manuel Koch

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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 interac- tions 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 g1 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.
Original languageEnglish
Article number13515
Number of pages53
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 30 Nov 2016

Keywords

  • Axon and dendritic guidance
  • Extracellular Matrix
  • X-ray Crystallography

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