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

DOI
Publisher DOI
PubMed ID
27901020
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 Issued
2016-11-30
Publication Type
Article
Subject(s)
Language(s)
en
Author(s)
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
Bloch, Wilhelm
Clausen-Schaumann, Hauke
Poschl, Ernst
Yurchenco, Peter D
Ehrbar, Martin
Mehlen, Patrick
Stetefeld, Jörg
Koch, Manuel
Additional Credits
Journal
Nature communications
Publisher
Nature Publishing Group
ISSN
2041-1723
Access(Rights)
open.access
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