title: MeCP2 binding to DNA depends upon hydration at methyl-CpG.
abstract: 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.
authors.affiliation: School of Biological Sciences, University of Edinburgh, King's Buildings, Mayfield Road, Edinburgh EH9 3JR, UK.
authors.forename: Kok Lian
authors.initials: KL
authors.lastname: Ho
authors.forename: Iain W
authors.initials: IW
authors.lastname: McNae
authors.forename: Lars
authors.initials: L
authors.lastname: Schmiedeberg
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Klose
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Bird
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Walkinshaw
mesh_terms: 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
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D046911:Macromolecular Substances; D051783:Methyl-CpG-Binding Protein 2; D004247:DNA; D013941:Thymine