Cited by 271Genomics and Chromatin DynamicsProtein Structure and DynamicsDNA and Nucleic Acid Chemistry

Structural Basis for the Versatile and Methylation-Dependent Binding of CTCF to DNA

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Hashimoto, Hideharu, Wang, Dongxue, Horton, John R., Zhang, Xing, Corces, Victor G., Cheng, Xiaodong·2017·Molecular Cell

Abstract

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.

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Crossref · 10.1016/j.molcel.2017.05.004

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  • This selective sensitivity to 5mC can be explained by the biophysical properties of CTCF's 11 zinc fingers, which make it sensitive to methylation of specific cytosines in its binding motif.

    “This selective 5mC sensitivity can be explained by the different biophysical property of CTCF’s 11 zinc fingers leading to its sensitivity to specific cytosine within its binding motif being methylated (31).”

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Authors
Hashimoto, H., Wang, D., Horton, J. R., Zhang, X., Corces, V. G., & Cheng, X.
Affiliations
  • Emory University (US)
  • The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Cheng, Xiaodong
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2017-06
Volume
66
Issue
5
Pages
711-720.e3
ISSN
1097-2765 (ISSN-L)
OpenAlex
W2614347829
Cited by
268
References
49
Citations by year
2026: 21 · 2025: 28 · 2024: 36 · 2023: 27 · 2022: 29 · 2021: 31 · 2020: 37 · 2019: 30 · 2018: 24 · 2017: 5
FWCI
10.72
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (GM049245-23)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Keywords
CTCF, zinc finger DNA-binding domain, cytosine methylation, sequence specificity, consensus sequence, hydrogen bonding, chromatin organization, protein-DNA interactions
MeSH terms
CCCTC-Binding Factor, Binding Sites, Cloning, Molecular, DNA, Humans, Hydrogen Bonding, Models, Molecular, Nucleic Acid Conformation, Protein Binding, Repressor Proteins, Structure-Activity Relationship, Zinc Fingers, Crystallography, X-Ray, Trinucleotide Repeats, DNA Methylation, 5-Methylcytosine, Protein Stability

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