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

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; Ernst Poschl; Peter D. Yurchenco; Martin Ehrbar; Patrick Mehlen; Jörg Stetefeld; Manuel Koch

doi:10.1038/ncomms13515

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

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, Ernst PoschlPeter D. Yurchenco, Martin Ehrbar, Patrick Mehlen, Jörg Stetefeld, Manuel Koch

^*Corresponding author for this work

38 Citations (Scopus)

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 Î 31 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.

Original language	English
Article number	13515
Journal	Nature Communications
Volume	7
Number of pages	17
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms13515
Publication status	Published - 30 Nov 2016
Externally published	Yes

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Reuten, R., Patel, T. R., McDougall, M., Rama, N., Nikodemus, D., Gibert, B., Delcros, J. G., Prein, C., Meier, M., Metzger, S., Zhou, Z., Kaltenberg, J., McKee, K. K., Bald, T., Tüting, T., Zigrino, P., Djonov, V., Bloch, W., Clausen-Schaumann, H., ... Koch, M. (2016). Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes. Nature Communications, 7, [13515]. https://doi.org/10.1038/ncomms13515

Reuten, R, Patel, TR, McDougall, M, Rama, N, Nikodemus, D, Gibert, B, Delcros, JG, Prein, C, Meier, M, Metzger, S, Zhou, Z, Kaltenberg, J, McKee, KK, Bald, T, Tüting, T, Zigrino, P, Djonov, V, Bloch, W, Clausen-Schaumann, H, Poschl, E, Yurchenco, PD, Ehrbar, M, Mehlen, P, Stetefeld, J & Koch, M 2016, 'Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes', Nature Communications, vol. 7, 13515. https://doi.org/10.1038/ncomms13515

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title = "Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes",

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 {\^I} 31 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.",

author = "Raphael Reuten and Patel, {Trushar R.} and Matthew McDougall and Nicolas Rama and Denise Nikodemus and Benjamin Gibert and Delcros, {Jean Guy} and Carina Prein and Markus Meier and St{\'e}phanie Metzger and Zhigang Zhou and Jennifer Kaltenberg and McKee, {Karen K.} and Tobias Bald and Thomas T{\"u}ting and Paola Zigrino and Valentin Djonov and Wilhelm Bloch and Hauke Clausen-Schaumann and Ernst Poschl and Yurchenco, {Peter D.} and Martin Ehrbar and Patrick Mehlen and J{\"o}rg Stetefeld and Manuel Koch",

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doi = "10.1038/ncomms13515",

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AU - Reuten, Raphael

AU - Patel, Trushar R.

AU - McDougall, Matthew

AU - Rama, Nicolas

AU - Nikodemus, Denise

AU - Gibert, Benjamin

AU - Delcros, Jean Guy

AU - Prein, Carina

AU - Meier, Markus

AU - Metzger, Stéphanie

AU - Zhou, Zhigang

AU - Kaltenberg, Jennifer

AU - McKee, Karen K.

AU - Bald, Tobias

AU - Tüting, Thomas

AU - Zigrino, Paola

AU - Djonov, Valentin

AU - Bloch, Wilhelm

AU - Clausen-Schaumann, Hauke

AU - Poschl, Ernst

AU - Yurchenco, Peter D.

AU - Ehrbar, Martin

AU - Mehlen, Patrick

AU - Stetefeld, Jörg

AU - Koch, Manuel

PY - 2016/11/30

Y1 - 2016/11/30

N2 - 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 Î 31 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.

AB - 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 Î 31 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.

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DO - 10.1038/ncomms13515

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SN - 2041-1723

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JO - Nature Communications

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

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