Myelin-associated glycoprotein

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.[5] MAG is believed to be involved in myelination during nerve regeneration in the PNS[6] and is vital for the long-term survival of the myelinated axons following myelinogenesis.[7] In the CNS MAG is one of three main myelin-associated inhibitors of axonal regeneration after injury,[8] making it an important protein for future research on neurogenesis in the CNS.

MAG
Identifiers
Aliases	MAG, GMA, S-SIGLEC-4A, SIGLEC4A, SPG75, myelin associated glycoprotein
External IDs	OMIM: 159460 MGI: 96912 HomoloGene: 1771 GeneCards: MAG
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.12 Start 35,292,125 bp[1] End 35,313,807 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7 B1|7 19.26 cM Start 30,899,176 bp[2] End 30,914,873 bp[2]
Gene ontology Molecular function • receptor binding • lipid binding • protein kinase binding • carbohydrate binding • sialic acid binding • protein homodimerization activity • ganglioside GT1b binding Cellular component • cytoplasm • cell membrane • integral component of plasma membrane • membrane • integral component of membrane • paranode region of axon • myelin sheath adaxonal region • myelin • compact myelin • Schmidt-Lanterman incisure • membrane raft • mesaxon Biological process • cell adhesion • nervous system development • negative regulation of neuron projection development • substantia nigra development • central nervous system myelination • negative regulation of axon extension • positive regulation of myelination • negative regulation of neuron apoptotic process • negative regulation of neuron differentiation • positive regulation of astrocyte differentiation • negative regulation of axonogenesis • leukocyte migration • cellular response to mechanical stimulus • cell-cell adhesion via plasma-membrane adhesion molecules • transmission of nerve impulse • axon regeneration Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4099	17136
Ensembl	ENSG00000105695	ENSMUSG00000036634
UniProt	P20916	P20917
RefSeq (mRNA)	NM_080600 NM_001199216 NM_002361	NM_010758 NM_001346084 NM_001346085 NM_001346086 NM_001346087 NM_001346088 NM_001346089 NM_001369262
RefSeq (protein)	NP_001186145 NP_002352 NP_542167	NP_001333013 NP_001333014 NP_001333015 NP_001333016 NP_001333017 NP_001333018 NP_034888 NP_001356191
Location (UCSC)	Chr 19: 35.29 – 35.31 Mb	Chr 7: 30.9 – 30.91 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

MAG is a 100 kDA glycoprotein.[9] Uncleaved MAG is a complete transmembrane form, which acts as a signaling and adhesion molecule.[10] 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.[11]

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.[12]

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.[13].\ Mutations to the MAG gene are implicated in demyelination diseases such as multiple sclerosis.[14]

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. [15] The mechanism responsible for inhibited neuroregeneration is regulated by three main proteins, one of which is MAG.[16] [17] 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.[18] MAG binds with high affinity to NgR, suggesting that it is equally as responsible for inhibition of axon regeneration as Nogo.[19]

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.[20]

See also

• Myelin
• Myelinogenesis
• NgR
• Myelin oligodendrocyte glycoprotein
• Anti-MAG peripheral neuropathy

External links

• Myelin-associated+glycoprotein at the US National Library of Medicine Medical Subject Headings (MeSH)

References

1. GRCh38: Ensembl release 89: ENSG00000105695 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000036634 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Quarles RH (March 2007). "Myelin-associated glycoprotein (MAG): past, present and beyond". Journal of Neurochemistry. 100 (6): 1431–48. doi:10.1111/j.1471-4159.2006.04319.x. PMID 17241126. S2CID 1544418.
6. Barton DE, Arquint M, Roder J, Dunn R, Francke U (October 1987). "The myelin-associated glycoprotein gene: mapping to human chromosome 19 and mouse chromosome 7 and expression in quivering mice". Genomics. 1 (2): 107–12. doi:10.1016/0888-7543(87)90002-4. PMID 2447011.
7. Bjartmar C, Yin X, Trapp BD (1999). "Axonal pathology in myelin disorders". Journal of Neurocytology. 28 (4–5): 383–95. doi:10.1023/a:1007010205037. PMID 10739578. S2CID 40528071.
8. McKerracher L, David S, Jackson DL, Kottis V, Dunn RJ, Braun PE (October 1994). "Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth". Neuron. 13 (4): 805–11. doi:10.1016/0896-6273(94)90247-x. PMID 7524558. S2CID 28429007.
9. Lopez PH (2014). "Role of myelin-associated glycoprotein (siglec-4a) in the nervous system". Advances in Neurobiology. 9: 245–62. doi:10.1007/978-1-4939-1154-7_11. ISBN 978-1-4939-1153-0. PMID 25151382.
10. Vinson M, Strijbos PJ, Rowles A, Facci L, Moore SE, Simmons DL, Walsh FS (June 2001). "Myelin-associated glycoprotein interacts with ganglioside GT1b. A mechanism for neurite outgrowth inhibition". The Journal of Biological Chemistry. 276 (23): 20280–5. doi:10.1074/jbc.M100345200. PMID 11279053.
11. Tang S, Shen YJ, DeBellard ME, Mukhopadhyay G, Salzer JL, Crocker PR, Filbin MT (September 1997). "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. doi:10.1083/jcb.138.6.1355. PMC 2132563. PMID 9298990.
12. Pronker MF, Lemstra S, Snijder J, Heck AJ, Thies-Weesie DM, Pasterkamp RJ, Janssen BJ (December 2016). "Structural basis of myelin-associated glycoprotein adhesion and signalling". Nature Communications. 7: 13584. doi:10.1038/ncomms13584. PMC 5150538. PMID 27922006.
13. Lopez PH (2014). "Role of myelin-associated glycoprotein (siglec-4a) in the nervous system". Advances in Neurobiology. 9: 245–62. doi:10.1007/978-1-4939-1154-7_11. ISBN 978-1-4939-1153-0. PMID 25151382.
14. Pronker MF, Lemstra S, Snijder J, Heck AJ, Thies-Weesie DM, Pasterkamp RJ, Janssen BJ (December 2016). "Structural basis of myelin-associated glycoprotein adhesion and signalling". Nature Communications. 7: 13584. doi:10.1038/ncomms13584. PMC 5150538. PMID 27922006.
15. Gage FH, Temple S (October 2013). "Neural stem cells: generating and regenerating the brain". Neuron. 80 (3): 588–601. doi:10.1016/j.neuron.2013.10.037. PMID 24183012.
16. McKerracher L, David S, Jackson DL, Kottis V, Dunn RJ, Braun PE (October 1994). "Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth". Neuron. 13 (4): 805–11. doi:10.1016/0896-6273(94)90247-x. PMID 7524558. S2CID 28429007.
17. Mukhopadhyay G, Doherty P, Walsh FS, Crocker PR, Filbin MT (September 1994). "A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration". Neuron. 13 (3): 757–67. doi:10.1016/0896-6273(94)90042-6. PMID 7522484. S2CID 928929.
18. Domeniconi M, Cao Z, Spencer T, Sivasankaran R, Wang K, Nikulina E, Kimura N, Cai H, Deng K, Gao Y, He Z, Filbin M (July 2002). "Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth". Neuron. 35 (2): 283–90. doi:10.1016/s0896-6273(02)00770-5. PMID 12160746. S2CID 17970421.
19. Liu BP, Fournier A, GrandPré T, Strittmatter SM (August 2002). "Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor". Science. 297 (5584): 1190–3. doi:10.1126/science.1073031. PMID 12089450. S2CID 1357777.
20. Kaplan DR, Miller FD (May 2003). "Axon growth inhibition: signals from the p75 neurotrophin receptor". Nature Neuroscience. 6 (5): 435–6. doi:10.1038/nn0503-435. PMID 12715005. S2CID 40563260.