title: Transcriptional repressor domain of MBD1 is intrinsically disordered and interacts with its binding partners in a selective manner.
abstract: Methylation of DNA CpG sites is a major mechanism of epigenetic gene silencing and plays important roles in cell division, development and carcinogenesis. One of its regulators is the 64-residue C-terminal Transcriptional Repressor Domain (the TRD) of MBD1, which recruits several repressor proteins such as MCAF1, HDAC3 and MPG that are essential for the gene silencing. Using NMR spectroscopy, we have characterized the solution structure of the C-terminus of MBD1 (MBD1-c, residues D507 to Q605), which included the TRD (A529 to P592). Surprisingly, the MBD1-c is intrinsically disordered. Despite its lack of a tertiary folding, MBD1-c could still bind to different partner proteins in a selective manner. MPG and MCAF1Δ8 showed binding to both the N-terminal and C-terminal residues of MBD1-c but HDAC3 preferably bound to the C-terminal region. This study reveals how MBD1-c discriminates different binding partners, and thus, expands our understanding of the mechanisms of gene regulation by MBD1.
authors.affiliation: 1] Department of Biological Sciences, National University of Singapore, Singapore 117543 [2].
authors.forename: Umar Farook Shahul
authors.initials: UF
authors.lastname: Hameed
authors.affiliation: 1] Department of Biological Sciences, National University of Singapore, Singapore 117543 [2].
authors.forename: Jackwee
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Mariusz A
authors.initials: MA
authors.lastname: Wasik
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore 117543.
authors.forename: Daiwen
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore 117543.
authors.forename: Kunchithapadam
authors.initials: K
authors.lastname: Swaminathan
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D000099186:Histone Deacetylase 3
chemical_list: D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D012097:Repressor Proteins; D014157:Transcription Factors; D000099186:Histone Deacetylase 3