Interaction of nuclear receptor zinc finger DNA binding domains with histone deacetylase.
A direct interaction between the nuclear receptor TR2 and histone deacetylases (HDACs) 3 and 4 is mediated by the DNA binding domain (DBD) of TR2. To test if this interaction is common to members of the nuclear receptor family, the Cys2-Cys2 type zinc finger (ZF) DBDs were subcloned from several nuclear receptors (mRARalpha, mRXRbeta, mTR2, mTR4, RAR, mPPARdelta, and mPPARgamma2). Using GST pull-downs, both HDACs 3 and 4 were found to interact directly with the core DBD from each receptor. The three-dimensional structure of the ZF domains was essential for this interaction as disruption by zinc chelation precluded interaction with HDACs. The results suggest that the ZFs of nuclear receptors provide a general interaction interface for HDACs 3 and 4. Functional significance of this interaction was demonstrated using ChIP assays where a truncated TR2 protein (lacking the LBD) recruited HDACs 3 and 4 to the target DNA causing demonstrable histone deacetylation. GST pull-downs and mammalian two-hybrid interaction tests were then used to define the interaction domains of HDAC3 with TR2. Both the N- and C-terminal portions of HDAC3 showed interaction with the TR2 DBD. Thus, multiple domains of HDAC3 form the interaction surface for the DBD of nuclear receptors.
Franco
Peter J
PJ
Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
Li
Guangjin
G
Wei
Li-Na
LN
D000818:Animals; D001665:Binding Sites; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D011485:Protein Binding; D025941:Protein Interaction Mapping; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D016335:Zinc Fingers; D000099186:Histone Deacetylase 3
D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C539822:NR2C1 protein, human; C539823:Nr2c1 protein, mouse; C400300:HDAC4 protein, human