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

Reuten, Raphael, Patel, Trushar R., Mcdougall, Matthew, Rama, Nicolas, Nikodemus, Denise, Gibert, Benjamin, Delcros, Jean-Guy, Prein, Carina, Meier, Markus, Metzger, Stéphanie, Zhou, Zhigang, Kaltenberg, Jennifer, Mckee, Karen K., Bald, Tobias, Tüting, Thomas, Zigrino, Paola, Djonov, Valentin, Bloch, Wilhelm, Clausen-Schaumann, Hauke, Poschl, Ernst, Yurchenco, Peter D., Ehrbar, Martin, Mehlen, Patrick, Stetefeld, Jörg and Koch, Manuel (2016) Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes. Nature Communications, 7. ISSN 2041-1723

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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.

Item Type: Article
Additional Information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Uncontrolled Keywords: axon and dendritic guidance,extracellular matrix,x-ray crystallography
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Biological Sciences
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Depositing User: Pure Connector
Date Deposited: 03 Dec 2016 00:01
Last Modified: 22 Apr 2020 01:54
URI: https://ueaeprints.uea.ac.uk/id/eprint/61591
DOI: 10.1038/ncomms13515

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