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

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 ₂His ₂ zinc finger protein implicated in tumor-cell prolifer...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-09, Vol.109 (38), p.15229-15234
Main Authors: Buck-Koehntop, Bethany A, Stanfield, Robyn L, Ekiert, Damian C, Martinez-Yamout, Maria A, Dyson, H. Jane, Wilson, Ian A, Wright, Peter E
Format: Article
Language:English
Subjects:
Base Sequence
Binding sites
Biological Sciences
cadherins
Cadherins - chemistry
Cancer
Cell growth
Cell lines
chromatin
Chromatin - chemistry
CpG Islands
Crystal structure
Crystallography, X-Ray - methods
DNA
DNA - chemistry
DNA Methylation
Epigenetics
Eukaryotes
eukaryotic cells
gene silencing
genes
genomic imprinting
Humans
hydrogen bonding
Hydrogen bonds
Hydrogen-Ion Concentration
Magnetic Resonance Spectroscopy - methods
Methylation
Molecular Conformation
Molecular Sequence Data
neoplasm cells
Nucleotide sequences
Phosphates
promoter regions
Promoter Regions, Genetic
Protein Binding
Protein Folding
Protein Structure, Tertiary
Proteins
Transcription Factors - chemistry
Transcription Factors - genetics
Zinc
zinc finger motif
Zinc Fingers
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Summary: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 ₂His 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1213726109