2wbu

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CRYSTAL STRUCTURE OF THE ZINC FINGER DOMAIN OF KLF4 BOUND TO ITS TARGET DNA

Structural highlights

2wbu is a 3 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.5Å
Ligands:ZN
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]

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

Krueppel-like factor 4 (Klf4) belongs to the Sp/Klf family of zinc-finger transcription factors and is indispensable for terminal maturation of epithelial tissues. Furthermore, it is part of a small set of proteins that are used to generate pluripotent embryonic stem cells from differentiated tissues. Herein, we describe that a Klf4 zinc-finger domain mutant induces self-renewal and block of maturation, while wild-type Klf4 induces terminal macrophage differentiation. Moreover, we present the crystal structure of the zinc-finger domain of Klf4 bound to its target DNA, revealing that primarily the two C-terminal zinc-finger motifs are required for site specificity. Lack of those two zinc fingers leads to deficiency of Klf4 to induce macrophage differentiation. The first zinc finger, on the other hand, inhibits the otherwise cryptic self-renewal and block of differentiation activity of Klf4. Our data show that impairing the DNA binding could potentially contribute to a monocytic leukemia.

The structure of the Klf4 DNA-binding domain links to self-renewal and macrophage differentiation.,Schuetz A, Nana D, Rose C, Zocher G, Milanovic M, Koenigsmann J, Blasig R, Heinemann U, Carstanjen D Cell Mol Life Sci. 2011 Sep;68(18):3121-31. Epub 2011 Feb 3. PMID:21290164[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ Schuetz A, Nana D, Rose C, Zocher G, Milanovic M, Koenigsmann J, Blasig R, Heinemann U, Carstanjen D. The structure of the Klf4 DNA-binding domain links to self-renewal and macrophage differentiation. Cell Mol Life Sci. 2011 Sep;68(18):3121-31. Epub 2011 Feb 3. PMID:21290164 doi:10.1007/s00018-010-0618-x

Contents


PDB ID 2wbu

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