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Structural basis of myelin-associated glycoprotein adhesion and signalling

Author

Listed:
  • 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)

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.

Suggested Citation

  • Matti F. Pronker & Suzanne Lemstra & Joost Snijder & Albert J. R. Heck & Dominique M. E. Thies-Weesie & R. Jeroen Pasterkamp & Bert J. C. Janssen, 2016. "Structural basis of myelin-associated glycoprotein adhesion and signalling," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13584
    DOI: 10.1038/ncomms13584
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    Cited by:

    1. Lucas M. P. Chataigner & Christos Gogou & Maurits A. Boer & Cátia P. Frias & Dominique M. E. Thies-Weesie & Joke C. M. Granneman & Albert J. R. Heck & Dimphna H. Meijer & Bert J. C. Janssen, 2022. "Structural insights into the contactin 1 – neurofascin 155 adhesion complex," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Edward N. Schmidt & Dimitra Lamprinaki & Kelli A. McCord & Maju Joe & Mirat Sojitra & Ayk Waldow & Jasmine Nguyen & John Monyror & Elena N. Kitova & Fahima Mozaneh & Xue Yan Guo & Jaesoo Jung & Jhon R, 2023. "Siglec-6 mediates the uptake of extracellular vesicles through a noncanonical glycolipid binding pocket," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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