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.
Highlights
Myelin-associated glycoprotein (MAG) is a myelin-expressed cell-adhesion and bi-directional signalling molecule
How MAG transduces the extracellular signal into the myelinating cell is not well understood, but it has been shown that the cytosolic domain of the L-MAG isoform binds to the cytoplasmic non-receptor tyrosine kinase Fyn[23] and that antibody-induced crosslinking of L-MAG triggers its localization to lipid rafts[24] and activates Fyn in oligodendrocytes[23]
Using a combination of structural, biophysical and cellular techniques, we provide the structural basis of MAG-mediated adhesion and identify a dimerization-dependent mechanism that explains how MAG regulates axon-to-myelin and myelin-to-axon signalling, and controls myelin–axon spacing
Summary
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. How MAG transduces the extracellular signal into the myelinating cell is not well understood, but it has been shown that the cytosolic domain of the L-MAG isoform binds to the cytoplasmic non-receptor tyrosine kinase Fyn[23] and that antibody-induced crosslinking of L-MAG triggers its localization to lipid rafts[24] and activates Fyn in oligodendrocytes[23]. This activation of Fyn is essential for the initiation of myelination[25].
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