Structural basis of myelin-associated glycoprotein adhesion and signalling

Matti F. Pronker, Suzanne Lemstra, Joost Snijder, Albert J. R. Heck, Dominique M. E. Thies-Weesie, R. Jeroen Pasterkamp and Bert J. C. Janssen ()
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Matti F. Pronker: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University
Suzanne Lemstra: Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100
Joost Snijder: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University
Albert J. R. Heck: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University
Dominique M. E. Thies-Weesie: Van’t Hoff Laboratory for Physical and Colloid Chemistry, Debye Institute of Nanomaterials Science, Faculty of Science, Utrecht University
R. Jeroen Pasterkamp: Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100
Bert J. C. Janssen: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13584

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