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

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

2016
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Overview
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. Netrins are secreted guidance factors that promote axon outgrowth and orientation during nervous system development. Here the authors present structural and biological evidence that netrin-4 is not a guidance cue per se, but rather functions to modulate laminin-laminin interactions.