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

Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15229-34. doi: 10.1073/pnas.1213726109. Epub 2012 Sep 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Base Sequence
  • Cadherins / chemistry
  • Chromatin / chemistry
  • CpG Islands
  • Crystallography, X-Ray / methods
  • DNA / chemistry
  • DNA Methylation
  • Humans
  • Hydrogen-Ion Concentration
  • Magnetic Resonance Spectroscopy / methods
  • Molecular Conformation
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Folding
  • Protein Structure, Tertiary
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics
  • Zinc Fingers

Substances

  • Cadherins
  • Chromatin
  • Transcription Factors
  • ZNF-kaiso protein, human
  • DNA

Associated data

  • PDB/2LT7
  • PDB/4F6M
  • PDB/4F6N