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

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Reuten, Raphael
Patel, Trushar R.
McDougall, Matthew
Rama, Nicolas
Nikodemus, Denise
Gibert, Benjamin
Delcros, Jean-Guy
Prein, Carina
Meier, Markus
Metzger, Stéphanie
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Nature Portfolio
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.
Open access article. Creative Commons Attribution 4.0 International license (CC BY 4.0) applies
Axon and dendritic guidance , Extracellular matrix , X-ray crystallography , Netrins , Netrin-4
Reuten, R., Patel, T. R., McDougall, M., Rama, N., Nikodemus, D., Gibert, B., Delcros, J.-G., Prein, C., Meier, M., Metzger, S., Zhou, Z., Kaltenberg, J., McKee, K. K., Bald, T., Tuting, T., Zigrino, P., Djonov, V., Bloch, W., Clausen-Schaumann, H., Poschl, E.,...Koch, M. (2016). Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes. Nature Communications, 7, Article 13515.