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

DOI: 10.1038/s41467-023-36692-w DOI Help

Authors: Markus Meier (University of Manitoba) , Monika Gupta (University of Manitoba) , Serife Akgül (University Hospital Cologne, University of Cologne; Max Planck Institute for Biology of Ageing) , Matthew Mcdougall (University of Manitoba) , Thomas Imhof (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 P. 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 (University of New South Wales; Max Delbrück Center for Molecular Medicine) , Adam Antebi (Max Planck Institute for Biology of Ageing; University of Cologne) , Manuel Koch (University Hospital Cologne, University of Cologne) , Jörg Stetefeld (University of Manitoba)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 14

State: Published (Approved)
Published: March 2023

Open Access Open Access

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.

Journal Keywords: Biophysical chemistry; Caenorhabditis elegans; Intracellular signalling peptides and proteins; X-ray crystallography

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: B21-High Throughput SAXS

Added On: 06/03/2023 11:23


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)