| Structural highlights
Function
[NDF1_MOUSE] Acts as a transcriptional activator: mediates transcriptional activation by binding to E box-containing promoter consensus core sequences 5'-CANNTG-3'. Associates with the p300/CBP transcription coactivator complex to stimulate transcription of the secretin gene as well as the gene encoding the cyclin-dependent kinase inhibitor CDKN1A. Contributes to the regulation of several cell differentiation pathways, like those that promote the formation of early retinal ganglion cells, inner ear sensory neurons, granule cells forming either the cerebellum or the dentate gyrus cell layer of the hippocampus, endocrine islet cells of the pancreas and enteroendocrine cells of the small intestine. Together with PAX6 or SIX3, is required for the regulation of amacrine cell fate specification. Also required for dendrite morphogenesis and maintenance in the cerebellar cortex. Associates with chromatin to enhancer regulatory elements in genes encoding key transcriptional regulators of neurogenesis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The ubiquitous class I basic helix-loop-helix (bHLH) factor E47 forms heterodimers with multiple tissue specific class II bHLH proteins to regulate distinct differentiation pathways. In order to define how class I- class II heterodimer partners are selected, we determined the crystal structure of the E47-NeuroD1-bHLH dimer in complex with the insulin promoter E-box sequence. Purification of the bHLH domain of E47-NeuroD1 indicates that E47 heterodimers are stable in solution. The interactions between E47 and NeuroD1 in the heterodimer are comparable to the interactions between E47 monomers in the homodimer, including hydrogen bonding, buried hydrophobic surface, and packing interactions. This is consistent with a model in which E47-NeuroD1 heterodimers are favored due to the instability of NeuroD1 homodimers. Although E47-NeuroD1 is oriented uniquely on the E-box sequence (CATCTG) within the promoter of the insulin gene, no direct contacts are observed with the central base pairs within this E-box sequence. We propose that concerted domain motions allow E47 to form specific base contacts in solution. NeuroD1 is restrained from adopting the same base contacts by an additional phosphate backbone interaction by the neurogenic-specific residue His115. Orienting E47-NeuroD1 on promoters may foster protein-protein contacts essential to initiate transcription.
Crystal structure of E47-NeuroD1/beta2 bHLH domain-DNA complex: heterodimer selectivity and DNA recognition.,Longo A, Guanga GP, Rose RB Biochemistry. 2008 Jan 8;47(1):218-29. Epub 2007 Dec 11. PMID:18069799[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev. 1997 Sep 15;11(18):2323-34. PMID:9308961
- ↑ Mutoh H, Naya FJ, Tsai MJ, Leiter AB. The basic helix-loop-helix protein BETA2 interacts with p300 to coordinate differentiation of secretin-expressing enteroendocrine cells. Genes Dev. 1998 Mar 15;12(6):820-30. PMID:9512516
- ↑ Miyata T, Maeda T, Lee JE. NeuroD is required for differentiation of the granule cells in the cerebellum and hippocampus. Genes Dev. 1999 Jul 1;13(13):1647-52. PMID:10398678
- ↑ Liu M, Pleasure SJ, Collins AE, Noebels JL, Naya FJ, Tsai MJ, Lowenstein DH. Loss of BETA2/NeuroD leads to malformation of the dentate gyrus and epilepsy. Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):865-70. PMID:10639171
- ↑ Kim WY, Fritzsch B, Serls A, Bakel LA, Huang EJ, Reichardt LF, Barth DS, Lee JE. NeuroD-null mice are deaf due to a severe loss of the inner ear sensory neurons during development. Development. 2001 Feb;128(3):417-26. PMID:11152640
- ↑ Inoue T, Hojo M, Bessho Y, Tano Y, Lee JE, Kageyama R. Math3 and NeuroD regulate amacrine cell fate specification in the retina. Development. 2002 Feb;129(4):831-42. PMID:11861467
- ↑ Moore KB, Schneider ML, Vetter ML. Posttranslational mechanisms control the timing of bHLH function and regulate retinal cell fate. Neuron. 2002 Apr 11;34(2):183-95. PMID:11970861
- ↑ Khoo S, Griffen SC, Xia Y, Baer RJ, German MS, Cobb MH. Regulation of insulin gene transcription by ERK1 and ERK2 in pancreatic beta cells. J Biol Chem. 2003 Aug 29;278(35):32969-77. Epub 2003 Jun 16. PMID:12810726 doi:http://dx.doi.org/10.1074/jbc.M301198200
- ↑ Lin CH, Stoeck J, Ravanpay AC, Guillemot F, Tapscott SJ, Olson JM. Regulation of neuroD2 expression in mouse brain. Dev Biol. 2004 Jan 1;265(1):234-45. PMID:14697366
- ↑ Dufton C, Marcora E, Chae JH, McCullough J, Eby J, Hausburg M, Stein GH, Khoo S, Cobb MH, Lee JE. Context-dependent regulation of NeuroD activity and protein accumulation. Mol Cell Neurosci. 2005 Apr;28(4):727-36. PMID:15797719 doi:http://dx.doi.org/10.1016/j.mcn.2004.12.004
- ↑ Seo S, Lim JW, Yellajoshyula D, Chang LW, Kroll KL. Neurogenin and NeuroD direct transcriptional targets and their regulatory enhancers. EMBO J. 2007 Dec 12;26(24):5093-108. Epub 2007 Nov 15. PMID:18007592 doi:http://dx.doi.org/10.1038/sj.emboj.7601923
- ↑ Neptune ER, Podowski M, Calvi C, Cho JH, Garcia JG, Tuder R, Linnoila RI, Tsai MJ, Dietz HC. Targeted disruption of NeuroD, a proneural basic helix-loop-helix factor, impairs distal lung formation and neuroendocrine morphology in the neonatal lung. J Biol Chem. 2008 Jul 25;283(30):21160-9. doi: 10.1074/jbc.M708692200. Epub 2008 , Mar 13. PMID:18339630 doi:http://dx.doi.org/10.1074/jbc.M708692200
- ↑ Roybon L, Deierborg T, Brundin P, Li JY. Involvement of Ngn2, Tbr and NeuroD proteins during postnatal olfactory bulb neurogenesis. Eur J Neurosci. 2009 Jan;29(2):232-43. doi: 10.1111/j.1460-9568.2008.06595.x. PMID:19200230 doi:http://dx.doi.org/10.1111/j.1460-9568.2008.06595.x
- ↑ Anderson KR, Torres CA, Solomon K, Becker TC, Newgard CB, Wright CV, Hagman J, Sussel L. Cooperative transcriptional regulation of the essential pancreatic islet gene NeuroD1 (beta2) by Nkx2.2 and neurogenin 3. J Biol Chem. 2009 Nov 6;284(45):31236-48. doi: 10.1074/jbc.M109.048694. Epub 2009, Sep 15. PMID:19759004 doi:http://dx.doi.org/10.1074/jbc.M109.048694
- ↑ Cherry TJ, Wang S, Bormuth I, Schwab M, Olson J, Cepko CL. NeuroD factors regulate cell fate and neurite stratification in the developing retina. J Neurosci. 2011 May 18;31(20):7365-79. doi: 10.1523/JNEUROSCI.2555-10.2011. PMID:21593321 doi:http://dx.doi.org/10.1523/JNEUROSCI.2555-10.2011
- ↑ Longo A, Guanga GP, Rose RB. Crystal structure of E47-NeuroD1/beta2 bHLH domain-DNA complex: heterodimer selectivity and DNA recognition. Biochemistry. 2008 Jan 8;47(1):218-29. Epub 2007 Dec 11. PMID:18069799 doi:http://dx.doi.org/10.1021/bi701527r
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