Premium
An Intrinsically Disordered Region of MBD2 Both Recruits the Histone Deacetylase Core Complex of NuRD and Modifies Kinetics of DNA Binding
Author(s) -
Williams David,
Desai Megha,
Ginder Gordon
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.712.14
Subject(s) - histone deacetylase , histone , chromatin , acetylation , dna methylation , epigenetics , chromatin remodeling , chemistry , dna , microbiology and biotechnology , biology , gene , gene expression , biochemistry
The MBD2 protein recruits and assembles the Nu cleosome R emodeling and D eacetylase (NuRD) complex and thereby uniquely combines binding specificity for methylated DNA with histone deacetylation and chromatin remodeling. This MBD2‐NuRD complex has been implicated in methylation dependent silencing of genes during development and aberrant silencing of tumor suppressor genes during carcinogenesis. We have previously characterized and determined the structures of a coiled‐coil and methylcytosine binding (MBD) domains of MBD2. More recently we have characterized an intrinsically disordered region (IDR) of ~120 amino acids linking the MBD and coiled‐coil. NMR, CD, and AUC analyses show that this region, MBD2 IDR , does not adopt a regular structure in isolation or in the context of full‐length protein. Yet the MBD2 IDR stably binds three proteins that form the histone deacetylase core of NuRD. The first two‐thirds of the MBD2 IDR are necessary and sufficient to bind the histone deacetylase core; while mutating two consecutive residues within this region abrogates binding and disrupts the function of MBD2 in cells. At the same time, adding the MBD2 IDR to the MBD2 MBD in vitro reduces the off rate and increases DNA binding affinity by ~100 fold. The MBD2 IDR does not adopt a regular fold in the presence of DNA thereby functioning as a fuzzy DNA binding region. Hence the MBD2 IDR plays a dual role both augmenting DNA binding affinity and recruiting a large portion of the NuRD complex.