The dynamic nature of netrin-1 and the structural basis for glycosaminoglycan fragment-induced filament formation

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, Philipp Kukura, Wenming Huang, Birgit Gerisch, Matthias Mörgelin, Kate Poole, Adam Antebi (), Manuel Koch () and Jörg Stetefeld ()
Additional contact information
Markus Meier: University of Manitoba
Monika Gupta: University of Manitoba
Serife Akgül: Faculty of Medicine and University Hospital Cologne, University of Cologne
Matthew McDougall: University of Manitoba
Thomas Imhof: Faculty of Medicine and University Hospital Cologne, University of Cologne
Denise Nikodemus: Albert Ludwigs University of Freiburg
Raphael Reuten: University of Freiburg
Aniel Moya-Torres: University of Manitoba
Vu To: University of Manitoba
Fraser Ferens: University of Manitoba
Fabian Heide: University of Manitoba
Gay Pauline Padilla-Meier: University of Manitoba
Philipp Kukura: University of Oxford
Wenming Huang: Max Planck Institute for Biology of Ageing
Birgit Gerisch: Max Planck Institute for Biology of Ageing
Matthias Mörgelin: Colzyx AB
Kate Poole: Max Delbrück Center for Molecular Medicine
Adam Antebi: Max Planck Institute for Biology of Ageing
Manuel Koch: Faculty of Medicine and University Hospital Cologne, University of Cologne
Jörg Stetefeld: University of Manitoba

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Netrin-1 is a bifunctional chemotropic guidance cue that plays key roles in diverse cellular processes including axon pathfinding, cell migration, adhesion, differentiation, and survival. Here, we present a molecular understanding of netrin-1 mediated interactions with glycosaminoglycan chains of diverse heparan sulfate proteoglycans (HSPGs) and short heparin oligosaccharides. Whereas interactions with HSPGs act as platform to co-localise netrin-1 close to the cell surface, heparin oligosaccharides have a significant impact on the highly dynamic behaviour of netrin-1. Remarkably, the monomer-dimer equilibrium of netrin-1 in solution is abolished in the presence of heparin oligosaccharides and replaced with highly hierarchical and distinct super assemblies leading to unique, yet unknown netrin-1 filament formation. In our integrated approach we provide a molecular mechanism for the filament assembly which opens fresh paths towards a molecular understanding of netrin-1 functions.

Date: 2023
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DOI: 10.1038/s41467-023-36692-w

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