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; ... (2016). Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes. Nature communications, 7(13515), p. 13515. Nature Publishing Group 10.1038/ncomms13515

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy > Topographical and Clinical Anatomy

UniBE Contributor:

Djonov, Valentin

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Language:

English

Submitter:

David Christian Haberthür

Date Deposited:

28 Dec 2016 10:31

Last Modified:

15 Jan 2017 02:14

Publisher DOI:

10.1038/ncomms13515

PubMed ID:

27901020

BORIS DOI:

10.7892/boris.91726

URI:

https://boris.unibe.ch/id/eprint/91726

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