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 & Manuel Koch

Nature Communications
2016 vol: 7 article number: 13515 doi: 10.1038/ncomms13515

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.

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Topics: Monolith – MicroScale Thermophoresis, MST, Proteins, Publications