Solution structure of the methyl-CpG binding domain of human MBD1 in complex with methylated DNA.
In vertebrates, the biological consequences of DNA methylation are often mediated by protein factors containing conserved methyl-CpG binding domains (MBDs). Mutations in the MBD protein MeCP2 cause the neurodevelopmental disease Rett syndrome. We report here the solution structure of the MBD of the human methylation-dependent transcriptional regulator MBD1 bound to methylated DNA. DNA binding causes a loop in MBD1 to fold into a major and novel DNA binding interface. Recognition of the methyl groups and CG sequence at the methylation site is due to five highly conserved residues that form a hydrophobic patch. The structure indicates how MBD may access nucleosomal DNA without encountering steric interference from core histones, and provides a basis to interpret mutations linked to Rett syndrome in MeCP2.
Ohki
I
I
Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, 630-0101, Nara, Japan.
Shimotake
N
N
Fujita
N
N
Jee
J
J
Ikegami
T
T
Nakao
M
M
Shirakawa
M
M
D000107:Acetylation; D001665:Binding Sites / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C066141:MBD1 protein, human; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins; D014157:Transcription Factors