AUC 2022

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Netrin-1 self-assembly into supramolecular structures and fibrils
Submitter: Markus Meier
Authors: Markus Meier, Gay Pauline Padilla-Meier, Monika Ghupta, Scott Legare, Fabian Heide, Jaime Thomas, Haben Gabir, Vu To, Matthew McDougall, Manuel Koch, Jörg Stetefeld
Corresponding Author: Markus Meier
Title: Netrin-1 self-assembly into supramolecular structures and fibrils
Contribution Type: Full Talk
Selected for Presentation Yes
Abstract: Netrin-1 is a secreted extracellular matrix protein with an ever growing number of functions being discovered. It was first identified as an axon guidance cue that - in tandem with its receptors DCC and UNC5 - attracts or repels growing axons during brain development. It is a survival factor suppressing p53 medited apoptosis if it is bound to its receptors and is therefore considered an oncogene especially for colorectal cancers. Furthermore, it is involved in angiogenesis, and is a pro-inflammatory factor in obesity and liver disease. Netrin-1 gradients are present in the tissue during embryonic development, but are also observed in the colonic epithelium during homeostasis and during peripheral nerve regeneration. Netrin-1 associates strongly with heparin and heparan sulfate chains allowing it to anchor and form gradients in the extracellular matrix. We discovered the formation of supramolecular structures of Netrin-1 in the presence of short heparin oligosaccharides using SEC-SAXS, SEC-MALS, sedimentation velocity, massphotometry, biolayer interferometry and X-ray crystallography. Further investigation by transmission electron microscopy revealed the formation of fibrils of up to 5 ┬Ám in length. We monitored fibril growth by dynamic light scattering and probed if the presence of heparin oligosaccharides is a pre-requisite for fibril formation.