5k5i

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Homo sapiens CCCTC-binding factor (CTCF) ZnF5-8 and DNA complex structure in space group P65Homo sapiens CCCTC-binding factor (CTCF) ZnF5-8 and DNA complex structure in space group P65

Structural highlights

5k5i is a 3 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.19Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CTCF_HUMAN Chromatin binding factor that binds to DNA sequence specific sites. Involved in transcriptional regulation by binding to chromatin insulators and preventing interaction between promoter and nearby enhancers and silencers. Acts as transcriptional repressor binding to promoters of vertebrate MYC gene and BAG1 gene. Also binds to the PLK and PIM1 promoters. Acts as a transcriptional activator of APP. Regulates APOA1/C3/A4/A5 gene cluster and controls MHC class II gene expression. Plays an essential role in oocyte and preimplantation embryo development by activating or repressing transcription. Seems to act as tumor suppressor. Plays a critical role in the epigenetic regulation. Participates in the allele-specific gene expression at the imprinted IGF2/H19 gene locus. On the maternal allele, binding within the H19 imprinting control region (ICR) mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to IGF2. Plays a critical role in gene silencing over considerable distances in the genome. Preferentially interacts with unmethylated DNA, preventing spreading of CpG methylation and maintaining methylation-free zones. Inversely, binding to target sites is prevented by CpG methylation. Plays a important role in chromatin remodeling. Can dimerize when it is bound to different DNA sequences, mediating long-range chromatin looping. Mediates interchromosomal association between IGF2/H19 and WSB1/NF1 and may direct distant DNA segments to a common transcription factory. Causes local loss of histone acetylation and gain of histone methylation in the beta-globin locus, without affecting transcription. When bound to chromatin, it provides an anchor point for nucleosomes positioning. Seems to be essential for homologous X-chromosome pairing. May participate with Tsix in establishing a regulatable epigenetic switch for X chromosome inactivation. May play a role in preventing the propagation of stable methylation at the escape genes from X- inactivation. Involved in sister chromatid cohesion. Associates with both centromeres and chromosomal arms during metaphase and required for cohesin localization to CTCF sites. Regulates asynchronous replication of IGF2/H19.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Publication Abstract from PubMed

The multidomain CCCTC-binding factor (CTCF), containing a tandem array of 11 zinc fingers (ZFs), modulates the three-dimensional organization of chromatin. We crystallized the human CTCF DNA-binding domain in complex with a known CTCF-binding site. While ZF2 does not make sequence-specific contacts, each finger of ZF3-7 contacts three bases of the 15-bp consensus sequence. Each conserved nucleotide makes base-specific hydrogen bonds with a particular residue. Most of the variable base pairs within the core sequence also engage in interactions with the protein. These interactions compensate for deviations from the consensus sequence, allowing CTCF to adapt to sequence variations. CTCF is sensitive to cytosine methylation at position 2, but insensitive at position 12 of the 15-bp core sequence. These differences can be rationalized structurally. Although included in crystallizations, ZF10 and ZF11 are not visible, while ZF8 and ZF9 span the backbone of the DNA duplex, conferring no sequence specificity but adding to overall binding stability.

Structural Basis for the Versatile and Methylation-Dependent Binding of CTCF to DNA.,Hashimoto H, Wang D, Horton JR, Zhang X, Corces VG, Cheng X Mol Cell. 2017 Jun 1;66(5):711-720.e3. doi: 10.1016/j.molcel.2017.05.004. Epub, 2017 May 18. PMID:28529057[11]

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

References

  1. ↑ Filippova GN, Fagerlie S, Klenova EM, Myers C, Dehner Y, Goodwin G, Neiman PE, Collins SJ, Lobanenkov VV. An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes. Mol Cell Biol. 1996 Jun;16(6):2802-13. PMID:8649389
  2. ↑ Filippova GN, Lindblom A, Meincke LJ, Klenova EM, Neiman PE, Collins SJ, Doggett NA, Lobanenkov VV. A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers. Genes Chromosomes Cancer. 1998 May;22(1):26-36. PMID:9591631
  3. ↑ Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT. CTCF, a candidate trans-acting factor for X-inactivation choice. Science. 2002 Jan 11;295(5553):345-7. Epub 2001 Dec 6. PMID:11743158 doi:http://dx.doi.org/10.1126/science.1065982
  4. ↑ Kurukuti S, Tiwari VK, Tavoosidana G, Pugacheva E, Murrell A, Zhao Z, Lobanenkov V, Reik W, Ohlsson R. CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2. Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10684-9. Epub 2006 Jun 30. PMID:16815976 doi:http://dx.doi.org/0600326103
  5. ↑ Renda M, Baglivo I, Burgess-Beusse B, Esposito S, Fattorusso R, Felsenfeld G, Pedone PV. Critical DNA binding interactions of the insulator protein CTCF: a small number of zinc fingers mediate strong binding, and a single finger-DNA interaction controls binding at imprinted loci. J Biol Chem. 2007 Nov 16;282(46):33336-45. Epub 2007 Sep 7. PMID:17827499 doi:http://dx.doi.org/M706213200
  6. ↑ Sun L, Huang L, Nguyen P, Bisht KS, Bar-Sela G, Ho AS, Bradbury CM, Yu W, Cui H, Lee S, Trepel JB, Feinberg AP, Gius D. DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation. Cancer Res. 2008 Apr 15;68(8):2726-35. PMID:18413740 doi:68/8/2726
  7. ↑ Majumder P, Gomez JA, Chadwick BP, Boss JM. The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions. J Exp Med. 2008 Apr 14;205(4):785-98. Epub 2008 Mar 17. PMID:18347100 doi:http://dx.doi.org/jem.20071843
  8. ↑ Fu Y, Sinha M, Peterson CL, Weng Z. The insulator binding protein CTCF positions 20 nucleosomes around its binding sites across the human genome. PLoS Genet. 2008 Jul 25;4(7):e1000138. PMID:18654629 doi:http://dx.doi.org/10.1371/journal.pgen.1000138
  9. ↑ Rubio ED, Reiss DJ, Welcsh PL, Disteche CM, Filippova GN, Baliga NS, Aebersold R, Ranish JA, Krumm A. CTCF physically links cohesin to chromatin. Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8309-14. Epub 2008 Jun 11. PMID:18550811 doi:http://dx.doi.org/0801273105
  10. ↑ Mishiro T, Ishihara K, Hino S, Tsutsumi S, Aburatani H, Shirahige K, Kinoshita Y, Nakao M. Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster. EMBO J. 2009 May 6;28(9):1234-45. Epub 2009 Mar 26. PMID:19322193 doi:http://dx.doi.org/emboj200981
  11. ↑ Hashimoto H, Wang D, Horton JR, Zhang X, Corces VG, Cheng X. Structural Basis for the Versatile and Methylation-Dependent Binding of CTCF to DNA. Mol Cell. 2017 Jun 1;66(5):711-720.e3. doi: 10.1016/j.molcel.2017.05.004. Epub, 2017 May 18. PMID:28529057 doi:http://dx.doi.org/10.1016/j.molcel.2017.05.004

5k5i, resolution 2.19Å

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