| Structural highlights
5kea is a 3 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| Related: | 5ke6, 5ke7, 5ke8, 5ke9, 5keb |
| Gene: | Klf4, Ezf, Gklf, Zie (LK3 transgenic mice) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[KLF4_MOUSE] Transcription factor; can act both as activator and as repressor. Binds the 5'-CACCC-3' core sequence. Binds to the promoter region of its own gene and can activate its own transcription. Regulates the expression of key transcription factors during embryonic development. Plays an important role in maintaining embryonic stem cells, and in preventing their differentiation. Required for establishing the barrier function of the skin and for postnatal maturation and maintenance of the ocular surface. Involved in the differentiation of epithelial cells and may also function in skeletal and kidney development. Contributes to the down-regulation of p53/TP53 transcription (By similarity).[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Reprogramming of mammalian genome methylation is critically important but poorly understood. Klf4, a transcription factor directing reprogramming, contains a DNA binding domain with three consecutive C2H2 zinc fingers. Klf4 recognizes CpG or TpG within a specific sequence. Mouse Klf4 DNA binding domain has roughly equal affinity for methylated CpG or TpG, and slightly lower affinity for unmodified CpG. The structural basis for this key preference is unclear, though the side chain of Glu446 is known to contact the methyl group of 5-methylcytosine (5mC) or thymine (5-methyluracil). We examined the role of Glu446 by mutagenesis. Substituting Glu446 with aspartate (E446D) resulted in preference for unmodified cytosine, due to decreased affinity for 5mC. In contrast, substituting Glu446 with proline (E446P) increased affinity for 5mC by two orders of magnitude. Structural analysis revealed hydrophobic interaction between the proline's aliphatic cyclic structure and the 5-methyl group of the pyrimidine (5mC or T). As in wild-type Klf4 (E446), the proline at position 446 does not interact directly with either the 5mC N4 nitrogen or the thymine O4 oxygen. In contrast, the unmethylated cytosine's exocyclic N4 amino group (NH2) and its ring carbon C5 atom hydrogen bond directly with the aspartate carboxylate of the E446D variant. Both of these interactions would provide a preference for cytosine over thymine, and the latter one could explain the E446D preference for unmethylated cytosine. Finally, we evaluated the ability of these Klf4 mutants to regulate transcription of methylated and unmethylated promoters in a luciferase reporter assay.
Distinctive Klf4 mutants determine preference for DNA methylation status.,Hashimoto H, Wang D, Steves AN, Jin P, Blumenthal RM, Zhang X, Cheng X Nucleic Acids Res. 2016 Sep 4. pii: gkw774. PMID:27596594[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mahatan CS, Kaestner KH, Geiman DE, Yang VW. Characterization of the structure and regulation of the murine gene encoding gut-enriched Kruppel-like factor (Kruppel-like factor 4). Nucleic Acids Res. 1999 Dec 1;27(23):4562-9. PMID:10556311
- ↑ Segre JA, Bauer C, Fuchs E. Klf4 is a transcription factor required for establishing the barrier function of the skin. Nat Genet. 1999 Aug;22(4):356-60. PMID:10431239 doi:http://dx.doi.org/10.1038/11926
- ↑ Li Y, McClintick J, Zhong L, Edenberg HJ, Yoder MC, Chan RJ. Murine embryonic stem cell differentiation is promoted by SOCS-3 and inhibited by the zinc finger transcription factor Klf4. Blood. 2005 Jan 15;105(2):635-7. Epub 2004 Sep 9. PMID:15358627 doi:http://dx.doi.org/10.1182/blood-2004-07-2681
- ↑ Nakatake Y, Fukui N, Iwamatsu Y, Masui S, Takahashi K, Yagi R, Yagi K, Miyazaki J, Matoba R, Ko MS, Niwa H. Klf4 cooperates with Oct3/4 and Sox2 to activate the Lefty1 core promoter in embryonic stem cells. Mol Cell Biol. 2006 Oct;26(20):7772-82. Epub 2006 Sep 5. PMID:16954384 doi:http://dx.doi.org/10.1128/MCB.00468-06
- ↑ Swamynathan SK, Katz JP, Kaestner KH, Ashery-Padan R, Crawford MA, Piatigorsky J. Conditional deletion of the mouse Klf4 gene results in corneal epithelial fragility, stromal edema, and loss of conjunctival goblet cells. Mol Cell Biol. 2007 Jan;27(1):182-94. Epub 2006 Oct 23. PMID:17060454 doi:http://dx.doi.org/10.1128/MCB.00846-06
- ↑ Wei Z, Yang Y, Zhang P, Andrianakos R, Hasegawa K, Lyu J, Chen X, Bai G, Liu C, Pera M, Lu W. Klf4 interacts directly with Oct4 and Sox2 to promote reprogramming. Stem Cells. 2009 Dec;27(12):2969-78. doi: 10.1002/stem.231. PMID:19816951 doi:http://dx.doi.org/10.1002/stem.231
- ↑ Zhang P, Andrianakos R, Yang Y, Liu C, Lu W. Kruppel-like factor 4 (Klf4) prevents embryonic stem (ES) cell differentiation by regulating Nanog gene expression. J Biol Chem. 2010 Mar 19;285(12):9180-9. doi: 10.1074/jbc.M109.077958. Epub 2010 , Jan 13. PMID:20071344 doi:http://dx.doi.org/10.1074/jbc.M109.077958
- ↑ Hashimoto H, Wang D, Steves AN, Jin P, Blumenthal RM, Zhang X, Cheng X. Distinctive Klf4 mutants determine preference for DNA methylation status. Nucleic Acids Res. 2016 Sep 4. pii: gkw774. PMID:27596594 doi:http://dx.doi.org/10.1093/nar/gkw774
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