Title : Structural basis of myelin-associated glycoprotein adhesion and signalling
Abstract :
Myelin-associated glycoprotein ( MAG ) is a myelin-expressed cell-adhesion and bi-directional signalling molecule
MAG maintains the myelin-axon spacing by interacting with specific neuronal glycolipids (gangliosides), inhibits axon regeneration and controls myelin formation
The mechanisms underlying MAG adhesion and signalling are unresolved
We present crystal structures of the MAG full ectodomain , which reveal an extended conformation of five Ig domains and a homodimeric arrangement involving membrane-proximal domains Ig4 and Ig5
MAG-oligosaccharide complex structures and biophysical assays show how MAG engages axonal gangliosides at domain Ig1
Two post-translational modifications were identified-N-linked glycosylation at the dimerization interface and tryptophan C-mannosylation proximal to the ganglioside binding site-that appear to have regulatory functions
Structure-guided mutations and neurite outgrowth assays demonstrate MAG dimerization and carbohydrate recognition are essential for its regeneration-inhibiting properties
The combination of trans ganglioside binding and cis homodimerization explains how MAG maintains the myelin-axon spacing and provides a mechanism for MAG-mediated bi-directional signalling