Myelin-associated glycoprotein explained

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, 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

Notes and References

  1. Quarles RH . Myelin-associated glycoprotein (MAG): past, present and beyond . Journal of Neurochemistry . 100 . 6 . 1431–48 . March 2007 . 17241126 . 10.1111/j.1471-4159.2006.04319.x . 1544418 .
  2. Barton DE, Arquint M, Roder J, Dunn R, Francke U . 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 . 2447011 . 10.1016/0888-7543(87)90002-4 . free .
  3. Bjartmar C, Yin X, Trapp BD . Axonal pathology in myelin disorders . Journal of Neurocytology . 1999 . 28 . 4–5 . 383–95 . 10739578 . 10.1023/a:1007010205037. 40528071 .
  4. McKerracher L, David S, Jackson DL, Kottis V, Dunn RJ, Braun PE . Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth . Neuron . 13 . 4 . 805–11 . October 1994 . 7524558 . 10.1016/0896-6273(94)90247-x. 28429007 .
  5. Book: Lopez PH . Role of Myelin-Associated Glycoprotein (Siglec-4a) in the Nervous System . Advances in Neurobiology . Glycobiology of the Nervous System . 2014 . 9 . 245–62 . 25151382 . 10.1007/978-1-4939-1154-7_11 . 978-1-4939-1153-0 .
  6. Vinson M, Strijbos PJ, Rowles A, Facci L, Moore SE, Simmons DL, Walsh FS . Myelin-associated glycoprotein interacts with ganglioside GT1b. A mechanism for neurite outgrowth inhibition . The Journal of Biological Chemistry . 276 . 23 . 20280–5 . June 2001 . 11279053 . 10.1074/jbc.M100345200 . free .
  7. Tang S, Shen YJ, DeBellard ME, Mukhopadhyay G, Salzer JL, Crocker PR, Filbin MT . 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 . 9298990 . 10.1083/jcb.138.6.1355. 2132563 .
  8. Pronker MF, Lemstra S, Snijder J, Heck AJ, Thies-Weesie DM, Pasterkamp RJ, Janssen BJ . Structural basis of myelin-associated glycoprotein adhesion and signalling . Nature Communications . 7 . 13584 . December 2016 . 27922006 . 10.1038/ncomms13584 . 5150538 . 2016NatCo...713584P .
  9. Book: Lopez PH . Role of Myelin-Associated Glycoprotein (Siglec-4a) in the Nervous System . Advances in Neurobiology . Glycobiology of the Nervous System . 2014 . 9 . 245–62 . 25151382 . 10.1007/978-1-4939-1154-7_11 . 978-1-4939-1153-0 .
  10. Pronker MF, Lemstra S, Snijder J, Heck AJ, Thies-Weesie DM, Pasterkamp RJ, Janssen BJ . Structural basis of myelin-associated glycoprotein adhesion and signalling . Nature Communications . 7 . 13584 . December 2016 . 27922006 . 10.1038/ncomms13584 . 5150538 . 2016NatCo...713584P .
  11. Gage FH, Temple S . Neural stem cells: generating and regenerating the brain . Neuron . 80 . 3 . 588–601 . October 2013 . 24183012 . 10.1016/j.neuron.2013.10.037 . free .
  12. McKerracher L, David S, Jackson DL, Kottis V, Dunn RJ, Braun PE . Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth . Neuron . 13 . 4 . 805–11 . October 1994 . 7524558 . 10.1016/0896-6273(94)90247-x. 28429007 .
  13. Mukhopadhyay G, Doherty P, Walsh FS, Crocker PR, Filbin MT . A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration . Neuron . 13 . 3 . 757–67 . September 1994 . 7522484 . 10.1016/0896-6273(94)90042-6. 928929 .
  14. Domeniconi M, Cao Z, Spencer T, Sivasankaran R, Wang K, Nikulina E, Kimura N, Cai H, Deng K, Gao Y, He Z, Filbin M . Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth . Neuron . 35 . 2 . 283–90 . July 2002 . 12160746 . 10.1016/s0896-6273(02)00770-5. 17970421 . free .
  15. Liu BP, Fournier A, GrandPré T, Strittmatter SM . Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor . Science . 297 . 5584 . 1190–3 . August 2002 . 12089450 . 10.1126/science.1073031 . 2002Sci...297.1190L . 1357777 . free .
  16. Kaplan DR, Miller FD . Axon growth inhibition: signals from the p75 neurotrophin receptor . Nature Neuroscience . 6 . 5 . 435–6 . May 2003 . 12715005 . 10.1038/nn0503-435 . 40563260 . free .

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