Cited by 128Epigenetics and DNA MethylationProtein Structure and DynamicsDNA and Nucleic Acid Chemistry

Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso

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Buck-Koehntop, Bethany A., Stanfield, Robyn L., Ekiert, Damian C., Martinez-Yamout, Maria A., Dyson, H. Jane, Wilson, Ian A., Wright, Peter E.·2012·Proceedings of the National Academy of Sciences

Abstract

Methylation of CpG dinucleotides in DNA is a common epigenetic modification in eukaryotes that plays a central role in maintenance of genome stability, gene silencing, genomic imprinting, development, and disease. Kaiso, a bifunctional Cys 2 His 2 zinc finger protein implicated in tumor-cell proliferation, binds to both methylated CpG (mCpG) sites and a specific nonmethylated DNA motif (TCCTGCNA) and represses transcription by recruiting chromatin remodeling corepression machinery to target genes. Here we report structures of the Kaiso zinc finger DNA-binding domain in complex with its nonmethylated, sequence-specific DNA target (KBS) and with a symmetrically methylated DNA sequence derived from the promoter region of E-cadherin . Recognition of specific bases in the major groove of the core KBS and mCpG sites is accomplished through both classical and methyl CH···O hydrogen-bonding interactions with residues in the first two zinc fingers, whereas residues in the C-terminal extension following the third zinc finger bind in the opposing minor groove and are required for high-affinity binding. The C-terminal region is disordered in the free protein and adopts an ordered structure upon binding to DNA. The structures of these Kaiso complexes provide insights into the mechanism by which a zinc finger protein can recognize mCpG sites as well as a specific, nonmethylated regulatory DNA sequence.

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Crossref · 10.1073/pnas.1213726109

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  • A bulky methyl group in the major groove leads to subtle widening of the major groove and narrowing of the minor groove.

    “the presence of a bulky methyl group in the major groove leads to a subtle widening of the major groove and a subtle narrowing of the minor groove.”
  • ZNF681 contains a classical C2H2 (Kruppel) zinc finger motif and functions as an activator and repressor of transcription, regulating proliferation, differentiation, and development.

    “Zinc finger protein 681 contains a classical C 2 H 2 (Kruppel) zinc finger motif and functions as an activator and repressor of transcription, regulating proliferation, differentiation, and development.38,49”

    From Altered genome-wide methylation in endometriosis (2014) · cites this paper as [49]

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Authors
Buck-Koehntop, B. A., Stanfield, R. L., Ekiert, D. C., Martinez-Yamout, M. A., Dyson, H. J., Wilson, I. A., & Wright, P. E.
Affiliations
  • Department of Molecular Biology and
  • Scripps Research Institute (US)
Venue
Proceedings of the National Academy of Sciences
Published
2012-09-04
Volume
109
Issue
38
Pages
15229-15234
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2021958912
Cited by
128
References
36
Citations by year
2026: 8 · 2025: 6 · 2024: 11 · 2023: 5 · 2022: 15 · 2021: 8 · 2020: 6 · 2019: 5 · 2018: 10 · 2017: 8 · 2016: 13 · 2015: 11 · 2014: 12 · 2013: 10
FWCI
4.24
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (Y1-CO-1020)
  • National Institute of General Medical Sciences (R01GM036643, Y1-GM-1104, GM036643)
  • National Center for Research Resources (P41RR001209)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • 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
Kaiso, C2H2 zinc finger, DNA methylation, CpG, sequence-specific DNA recognition, transcriptional repression, E-cadherin promoter, C-terminal extension, protein-DNA complex
MeSH terms
Base Sequence, Chromatin, DNA, Humans, Hydrogen-Ion Concentration, Molecular Conformation, Molecular Sequence Data, Magnetic Resonance Spectroscopy, Promoter Regions, Genetic, Protein Binding, Transcription Factors, Cadherins, Zinc Fingers, Protein Structure, Tertiary, Protein Folding, Crystallography, X-Ray, CpG Islands, DNA Methylation

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