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Nat Commun. 2016 Nov 30;7:13515. doi: 10.1038/ncomms13515.

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

Author information

1
Institute for Dental Research and Oral Musculoskeletal Biology, Medical Faculty, University of Cologne, Joseph-Stelzmann-Strasse 52, Cologne 50931, Germany.
2
Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Joseph-Stelzmann-Strasse 52, Cologne 50931, Germany.
3
Alberta RNA Research and Training Institute, Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive, Lethbridge, Alberta T1K 3M4, Canada.
4
School of Biosciences, University of Birmingham, Edgbaston B15 2TT, UK.
5
Department of Chemistry, University of Manitoba, Winnipeg R3T 2N2, Canada.
6
Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, Lyon 69008, France.
7
Center for Applied Tissue Engineering and Regenerative Medicine-CANTER, Munich University of Applied Sciences, Lothstrasse 34, Munich D-80335, Germany.
8
Laboratory of Experimental Surgery and Regenerative Medicine - ExperiMed, Department of Surgery, Clinical Center University of Munich, Nussbaumstrasse 20, Munich D-80336, Germany.
9
Center for Nanoscience-CeNS, Geschwister-Scholl-Platz 1, Munich D-80539, Germany.
10
Laboratory for Cell and Tissue Engineering, Department of Obstetrics, University Hospital Zurich, Schmelzbergstr. 12, Zurich 8091, Switzerland.
11
School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.
12
Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.
13
Department of Pathology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
14
Department of Dermatology, University Hospital Magdeburg, Magdeburg 39120, Germany.
15
Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, Bonn 53105, Germany.
16
Department of Dermatology and Venerology, University of Cologne, Cologne 50931, Germany.
17
Institute of Anatomy, University of Bern, Baltzerstrasse 2, Bern 3000, Switzerland.
18
Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Cologne 50933, Germany.

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.

PMID:
27901020
PMCID:
PMC5141367
DOI:
10.1038/ncomms13515
[Indexed for MEDLINE]
Free PMC Article

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