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

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Authors

  • 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
  • Peter D. Yurchenco
  • Martin Ehrbar
  • Patrick Mehlen
  • Jörg Stetefeld
  • Manuel Koch

Organisational units

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.

Details

Original languageEnglish
Article number13515
Number of pages53
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 30 Nov 2016
Peer-reviewedYes

Keywords

    Research areas

  • Axon and dendritic guidance, Extracellular Matrix, X-ray Crystallography

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