Biology Reference
In-Depth Information
FIGURE 2.1
Structural and functional organization on nuclear receptors. The structural organization of the
DBDand LBD is illustratedby the crystal structures of theRXRa-RARa DBDheterodimer bound
to a DR1 response element (Protein Data Bank code 1dsz) and the 9-cis-retinoic acid-bound
RXRa-RARa LBD heterodimer (Protein Data Bank code 1xdk). Helices are represented as
ribbons and labeled fromH1 toH12 (LBD) or H1 andH2 (DBD). 9-cis-retinoic acid inRARa and
RXRa LBDs is representedby yellowand redspheres. Thegrayspheres in theDBD indicateZn
2þ
ions. Residues mediating the weak DBD intersubunit contacts are displayed in yellow. The
cysteine residues coordinating the Zn
2þ
ions are shown in violet.
All NR proteins exhibit a characteristic modular structure that consists of five to
six domains of homology (designated A-F, from the N-terminal to the C-terminal)
based on regions of conserved sequence and function (
Fig. 2.1
). The DNA-binding
domain (DBD; region C) is the most highly conserved domain and encodes two zinc
finger modules. The ligand-binding domain (LBD; region E) is less conserved and
mediates ligand binding, dimerization, and a ligand-dependent transactivation func-
tion, termed AF-2. The N-terminal A-B region contains a cell- and promoter-specific
transactivation function termed AF-1. The region D is considered as a hinge domain.
The F region is not present in all receptors and its function is poorly understood.
Except for the dosage-sensitive sex reversal, adrenal hypoplasia congenital critical
region on the X chromosome gene 1 (DAX-1 (NR0B1)), and the short heterodimer
partner (SHP (NR0B2)), which both lack an essential DBD, NRs can bind their cog-
nate sequence-specific promoter elements on target genes either as monomers,
homodimers, or heterodimers with retinoid X receptors (RXR
a
(NR2B1), RXR
b
(NR2B2), and RXR
g
(NR2B3)). They all recognize the same hexameric DNA
core motif, 5
0
-PuGGTCA (Pu
A or G), but mutation, extension, duplication, and
distinct relative orientations of repeats of this motif have generated response
elements that are selective for a given class of receptors. For example, the RXR-
RAR heterodimers bind to retinoic acid response elements that mainly correspond
to direct repeats of the motif 5
0
-AGGTCA separated by five, two, or one nucleotides
(referred to as DR5, DR2, and DR1;
Fig. 2.1
), whereas steroid receptors such as the
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