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

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  • Raphael Reuten

    (Institute for Dental Research and Oral Musculoskeletal Biology, Medical Faculty, University of Cologne
    Center for Biochemistry, Medical Faculty, University of Cologne, Cologne
    Present address: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), Copenhagen DK-2200, Denmark)

  • Trushar R. Patel

    (Alberta RNA Research and Training Institute, University of Lethbridge
    School of Biosciences, University of Birmingham)

  • Matthew McDougall

    (University of Manitoba)

  • Nicolas Rama

    (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)

  • Denise Nikodemus

    (Institute for Dental Research and Oral Musculoskeletal Biology, Medical Faculty, University of Cologne
    Center for Biochemistry, Medical Faculty, University of Cologne, Cologne)

  • Benjamin Gibert

    (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)

  • Jean-Guy Delcros

    (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)

  • Carina Prein

    (Center for Applied Tissue Engineering and Regenerative Medicine–CANTER, Munich University of Applied Sciences
    Laboratory of Experimental Surgery and Regenerative Medicine – ExperiMed, Clinical Center University of Munich
    Center for Nanoscience—CeNS)

  • Markus Meier

    (University of Manitoba)

  • Stéphanie Metzger

    (Laboratory for Cell and Tissue Engineering, University Hospital Zurich)

  • Zhigang Zhou

    (School of Biological Sciences, University of East Anglia, Norwich Research Park
    Norwich Medical School, University of East Anglia, Norwich Research Park)

  • Jennifer Kaltenberg

    (Institute for Dental Research and Oral Musculoskeletal Biology, Medical Faculty, University of Cologne
    Center for Biochemistry, Medical Faculty, University of Cologne, Cologne)

  • Karen K. McKee

    (Robert Wood Johnson Medical School)

  • Tobias Bald

    (University Hospital Magdeburg
    Laboratory of Experimental Dermatology, University of Bonn)

  • Thomas Tüting

    (University Hospital Magdeburg
    Laboratory of Experimental Dermatology, University of Bonn)

  • Paola Zigrino

    (University of Cologne)

  • Valentin Djonov

    (Institute of Anatomy, University of Bern)

  • Wilhelm Bloch

    (Institute of Cardiovascular Research and Sport Medicine, German Sport University Cologne)

  • Hauke Clausen-Schaumann

    (Center for Applied Tissue Engineering and Regenerative Medicine–CANTER, Munich University of Applied Sciences
    Center for Nanoscience—CeNS)

  • Ernst Poschl

    (School of Biological Sciences, University of East Anglia, Norwich Research Park)

  • Peter D. Yurchenco

    (Robert Wood Johnson Medical School)

  • Martin Ehrbar

    (Laboratory for Cell and Tissue Engineering, University Hospital Zurich)

  • Patrick Mehlen

    (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)

  • Jörg Stetefeld

    (University of Manitoba)

  • Manuel Koch

    (Institute for Dental Research and Oral Musculoskeletal Biology, Medical Faculty, University of Cologne
    Center for Biochemistry, Medical Faculty, University of Cologne, Cologne)

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.

Suggested Citation

  • 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, 2016. "Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes," Nature Communications, Nature, vol. 7(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13515
    DOI: 10.1038/ncomms13515
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    Cited by:

    1. Lingchi Kong & Xin Gao & Xiangyun Yao & Haijiao Xie & Qinglin Kang & Wei Sun & Zhengwei You & Yun Qian & Cunyi Fan, 2024. "Multilevel neurium-mimetic individualized graft via additive manufacturing for efficient tissue repair," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Markus Meier & Monika Gupta & Serife Akgül & Matthew McDougall & Thomas Imhof & Denise Nikodemus & Raphael Reuten & Aniel Moya-Torres & Vu To & Fraser Ferens & Fabian Heide & Gay Pauline Padilla-Meier, 2023. "The dynamic nature of netrin-1 and the structural basis for glycosaminoglycan fragment-induced filament formation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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