MeCP2 binding to DNA depends upon hydration at methyl-CpG.
MeCP2 is an essential transcriptional repressor that mediates gene silencing through binding to methylated DNA. Binding specificity has been thought to depend on hydrophobic interactions between cytosine methyl groups and a hydrophobic patch within the methyl-CpG-binding domain (MBD). X-ray analysis of a methylated DNA-MBD cocrystal reveals, however, that the methyl groups make contact with a predominantly hydrophilic surface that includes tightly bound water molecules. This suggests that MeCP2 recognizes hydration of the major groove of methylated DNA rather than cytosine methylation per se. The MeCP2-DNA complex also identifies a unique structural role for T158, the residue most commonly mutated in Rett syndrome.
Ho
Kok Lian
KL
School of Biological Sciences, University of Edinburgh, King's Buildings, Mayfield Road, Edinburgh EH9 3JR, UK.
McNae
Iain W
IW
Schmiedeberg
Lars
L
Klose
Robert J
RJ
Bird
Adrian P
AP
Walkinshaw
Malcolm D
MD
D000595:Amino Acid Sequence; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D018899:CpG Islands; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D006801:Humans; D046911:Macromolecular Substances / Q000737:chemistry / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009690:Nucleic Acid Conformation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D015518:Rett Syndrome / Q000235:genetics; D016415:Sequence Alignment; D013941:Thymine / Q000737:chemistry / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D046911:Macromolecular Substances; D051783:Methyl-CpG-Binding Protein 2; D004247:DNA; D013941:Thymine