| Structural highlights
Function
[MYRF_MOUSE] Myelin regulatory factor: Constitutes a precursor of the transcription factor. Mediates the autocatalytic cleavage that releases the Myelin regulatory factor, N-terminal component that specifically activates transcription of central nervous system (CNS) myelin genes.[1] Myelin regulatory factor, C-terminal: Membrane-bound part that has no transcription factor activity and remains attached to the endoplasmic reticulum membrane following cleavage.[2] Myelin regulatory factor, N-terminal: Transcription factor that specifically activates expression of myelin genes such as MBP, MOG, MAG, DUSP15 and PLP1 during oligodendrocyte (OL) maturation, thereby playing a central role in oligodendrocyte maturation and CNS myelination (PubMed:19596243, PubMed:22956843, PubMed:23966833, PubMed:24204311, PubMed:27532821). Specifically recognizes and binds DNA sequence 5'-CTGGYAC-3' in the regulatory regions of myelin-specific genes and directly activates their expression. Not only required during oligodendrocyte differentiation but is also required on an ongoing basis for the maintenance of expression of myelin genes and for the maintenance of a mature, viable oligodendrocyte phenotype (PubMed:19596243, PubMed:22956843, PubMed:23966833).[3] [4] [5] [6] [7]
Publication Abstract from PubMed
Myelin-gene Regulatory Factor (MyRF) is one of the master transcription factors controlling myelin formation and development in oligodendrocytes which is crucial for the powerful brain functions. The N-terminal of MyRF, which contains a proline-rich region and a DNA binding domain (DBD), is auto-cleaved from the ER membrane, and then enters the nucleus to participate in transcription regulation of the myelin genes. Here we report the crystal structure of MyRF DBD. It shows an Ig-fold like architecture which consists of two antiparallel beta-sheets with 7 main strands, packing against each other, forming a beta-sandwich. Compared to its homolog, Ndt80, MyRF has a smaller and less complex DBD lacking the helices and the big loops outside the core. Structural alignment reveals that MyRF DBD possess less interaction sites with DNA than Ndt80 and may bind only at the major groove of DNA. Moreover, the structure reveals a trimeric assembly, agreeing with the previous report that MyRF DBD functions as a trimer. The mutant that we designed based on the structure disturbed trimer formation, but didn't affect the auto-cleavage reaction. It demonstrates that the activation of self-cleavage reaction of MyRF is independent of the presence of its N-terminal DBD homotrimer. The structure reported here will help to understand the molecular mechanism underlying the important roles of MyRF in myelin formation and development.
Crystal structure of the DNA-binding domain of Myelin-gene Regulatory Factor.,Zhen X, Li B, Hu F, Yan S, Meloni G, Li H, Shi N Sci Rep. 2017 Jun 16;7(1):3696. doi: 10.1038/s41598-017-03768-9. PMID:28623291[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bujalka H, Koenning M, Jackson S, Perreau VM, Pope B, Hay CM, Mitew S, Hill AF, Lu QR, Wegner M, Srinivasan R, Svaren J, Willingham M, Barres BA, Emery B. MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. PLoS Biol. 2013;11(8):e1001625. doi: 10.1371/journal.pbio.1001625. Epub 2013 Aug , 13. PMID:23966833 doi:http://dx.doi.org/10.1371/journal.pbio.1001625
- ↑ Bujalka H, Koenning M, Jackson S, Perreau VM, Pope B, Hay CM, Mitew S, Hill AF, Lu QR, Wegner M, Srinivasan R, Svaren J, Willingham M, Barres BA, Emery B. MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. PLoS Biol. 2013;11(8):e1001625. doi: 10.1371/journal.pbio.1001625. Epub 2013 Aug , 13. PMID:23966833 doi:http://dx.doi.org/10.1371/journal.pbio.1001625
- ↑ Emery B, Agalliu D, Cahoy JD, Watkins TA, Dugas JC, Mulinyawe SB, Ibrahim A, Ligon KL, Rowitch DH, Barres BA. Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell. 2009 Jul 10;138(1):172-85. doi: 10.1016/j.cell.2009.04.031. PMID:19596243 doi:http://dx.doi.org/10.1016/j.cell.2009.04.031
- ↑ Koenning M, Jackson S, Hay CM, Faux C, Kilpatrick TJ, Willingham M, Emery B. Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS. J Neurosci. 2012 Sep 5;32(36):12528-42. doi: 10.1523/JNEUROSCI.1069-12.2012. PMID:22956843 doi:http://dx.doi.org/10.1523/JNEUROSCI.1069-12.2012
- ↑ Bujalka H, Koenning M, Jackson S, Perreau VM, Pope B, Hay CM, Mitew S, Hill AF, Lu QR, Wegner M, Srinivasan R, Svaren J, Willingham M, Barres BA, Emery B. MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. PLoS Biol. 2013;11(8):e1001625. doi: 10.1371/journal.pbio.1001625. Epub 2013 Aug , 13. PMID:23966833 doi:http://dx.doi.org/10.1371/journal.pbio.1001625
- ↑ Hornig J, Frob F, Vogl MR, Hermans-Borgmeyer I, Tamm ER, Wegner M. The transcription factors Sox10 and Myrf define an essential regulatory network module in differentiating oligodendrocytes. PLoS Genet. 2013 Oct;9(10):e1003907. doi: 10.1371/journal.pgen.1003907. Epub 2013, Oct 31. PMID:24204311 doi:http://dx.doi.org/10.1371/journal.pgen.1003907
- ↑ Muth KN, Piefke S, Weider M, Sock E, Hermans-Borgmeyer I, Wegner M, Kuspert M. The Dual-specificity phosphatase Dusp15 is regulated by Sox10 and Myrf in Myelinating Oligodendrocytes. Glia. 2016 Dec;64(12):2120-2132. doi: 10.1002/glia.23044. Epub 2016 Aug 17. PMID:27532821 doi:http://dx.doi.org/10.1002/glia.23044
- ↑ Zhen X, Li B, Hu F, Yan S, Meloni G, Li H, Shi N. Crystal structure of the DNA-binding domain of Myelin-gene Regulatory Factor. Sci Rep. 2017 Jun 16;7(1):3696. doi: 10.1038/s41598-017-03768-9. PMID:28623291 doi:http://dx.doi.org/10.1038/s41598-017-03768-9
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