Biology:Myelin-associated glycoprotein

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Myelin-associated glycoprotein (MAG, Siglec-4) is a type 1 transmembrane protein glycoprotein localized in periaxonal Schwann cell and oligodendrocyte membranes, where it plays a role in glial-axonal interactions. MAG is a member of the SIGLEC family of proteins and is a functional ligand of the NOGO-66 receptor, NgR.[1] MAG is believed to be involved in myelination during nerve regeneration in the PNS[2] and is vital for the long-term survival of the myelinated axons following myelinogenesis.[3] In the CNS MAG is one of three main myelin-associated inhibitors of axonal regeneration after injury,[4] making it an important protein for future research on neurogenesis in the CNS.

Structure

MAG is a 100 kDA glycoprotein.[5] Uncleaved MAG is a complete transmembrane form, which acts as a signaling and adhesion molecule.[6] MAG can also act as a signaling molecule as a soluble protein after it has been proteolytically shed. This form of the protein is called dMAG.[7]

Adhesion

MAG has an extended conformation of five immunoglobulin (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.[8]

Function

Myelin-axon interactions

MAG is a critical protein in the formation and maintenance of myelin sheaths. MAG is localized on the inner membrane of the myelin sheath and interacts with axonal membrane proteins to attach the myelin sheath to the axon.[9].\ Mutations to the MAG gene are implicated in demyelination diseases such as multiple sclerosis.[10]

Inhibition of nerve regeneration

Axons in the central nervous system do not regenerate after injury the same way that axons in the peripheral nervous system do. [11] The mechanism responsible for inhibited neuroregeneration is regulated by three main proteins, one of which is MAG.[12] [13] The exact mechanism through which MAG inhibits neuroregeneration appears to be through binding of NgR. This receptor is also bound by Nogo protein, suggesting that the mechanism of myelin-associated inhibition of axon regeneration through NgR the has redundant ligands[clarification needed], furthering the inhibition.[14] MAG binds with high affinity to NgR, suggesting that it is equally as responsible for inhibition of axon regeneration as Nogo.[15]

Rho kinase pathway

Once MAG (or Nogo) has bound to NgR, NgR activates the rho kinase (ROCK) pathway. The activation of the rho kinase pathway leads to the phosphorylation of proteins which inhibit neurite outgrowth.[16]

See also

External links

References

  1. ↑ "Myelin-associated glycoprotein (MAG): past, present and beyond". Journal of Neurochemistry 100 (6): 1431–48. March 2007. doi:10.1111/j.1471-4159.2006.04319.x. PMID 17241126. 
  2. ↑ "The myelin-associated glycoprotein gene: mapping to human chromosome 19 and mouse chromosome 7 and expression in quivering mice". Genomics 1 (2): 107–12. October 1987. doi:10.1016/0888-7543(87)90002-4. PMID 2447011. 
  3. ↑ "Axonal pathology in myelin disorders". Journal of Neurocytology 28 (4–5): 383–95. 1999. doi:10.1023/a:1007010205037. PMID 10739578. 
  4. ↑ "Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth". Neuron 13 (4): 805–11. October 1994. doi:10.1016/0896-6273(94)90247-x. PMID 7524558. 
  5. ↑ "Role of Myelin-Associated Glycoprotein (Siglec-4a) in the Nervous System". Glycobiology of the Nervous System. Advances in Neurobiology. 9. 2014. pp. 245–62. doi:10.1007/978-1-4939-1154-7_11. ISBN 978-1-4939-1153-0. 
  6. ↑ "Myelin-associated glycoprotein interacts with ganglioside GT1b. A mechanism for neurite outgrowth inhibition". The Journal of Biological Chemistry 276 (23): 20280–5. June 2001. doi:10.1074/jbc.M100345200. PMID 11279053. 
  7. ↑ "Myelin-associated glycoprotein interacts with neurons via a sialic acid binding site at ARG118 and a distinct neurite inhibition site". The Journal of Cell Biology 138 (6): 1355–66. September 1997. doi:10.1083/jcb.138.6.1355. PMID 9298990. 
  8. ↑ "Structural basis of myelin-associated glycoprotein adhesion and signalling". Nature Communications 7: 13584. December 2016. doi:10.1038/ncomms13584. PMID 27922006. Bibcode: 2016NatCo...713584P. 
  9. ↑ "Role of Myelin-Associated Glycoprotein (Siglec-4a) in the Nervous System". Glycobiology of the Nervous System. Advances in Neurobiology. 9. 2014. pp. 245–62. doi:10.1007/978-1-4939-1154-7_11. ISBN 978-1-4939-1153-0. 
  10. ↑ "Structural basis of myelin-associated glycoprotein adhesion and signalling". Nature Communications 7: 13584. December 2016. doi:10.1038/ncomms13584. PMID 27922006. Bibcode: 2016NatCo...713584P. 
  11. ↑ "Neural stem cells: generating and regenerating the brain". Neuron 80 (3): 588–601. October 2013. doi:10.1016/j.neuron.2013.10.037. PMID 24183012. 
  12. ↑ "Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth". Neuron 13 (4): 805–11. October 1994. doi:10.1016/0896-6273(94)90247-x. PMID 7524558. 
  13. ↑ "A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration". Neuron 13 (3): 757–67. September 1994. doi:10.1016/0896-6273(94)90042-6. PMID 7522484. 
  14. ↑ "Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth". Neuron 35 (2): 283–90. July 2002. doi:10.1016/s0896-6273(02)00770-5. PMID 12160746. 
  15. ↑ "Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor". Science 297 (5584): 1190–3. August 2002. doi:10.1126/science.1073031. PMID 12089450. Bibcode: 2002Sci...297.1190L. 
  16. ↑ "Axon growth inhibition: signals from the p75 neurotrophin receptor". Nature Neuroscience 6 (5): 435–6. May 2003. doi:10.1038/nn0503-435. PMID 12715005. 



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