The nuclear receptor superfamily
Marc Robinson-Rechavi*,
Hector Escriva Garcia and
Vincent Laudet
Laboratoire de Biologie Moléculaire et Cellulaire, UMR CNRS 5665,
Ecole Normale Supérieure de Lyon, 46 allée d'Italie, 69364 Lyon
Cedex 07, France
*
Author for correspondence (e-mail:
marc.robinson{at}ens-lyon.fr)
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Introduction
|
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Nuclear receptors are one of the most abundant classes of transcriptional
regulators in animals (metazoans). They regulate diverse functions, such as
homeostasis, reproduction, development and metabolism (for a review, see
Laudet and Gronemeyer, 2002
).
Nuclear hormone receptors function as ligand-activated transcription factors,
and thus provide a direct link between signaling molecules that control these
processes and transcriptional responses. A large number of nuclear receptors
have been identified through sequence similarity to known receptors, but have
no identified natural ligand, and are referred to as `nuclear orphan
receptors'. As nuclear receptors bind small molecules that can easily be
modified by drug design, and control functions associated with major diseases
(e.g. cancer, osteoporosis and diabetes), they are promising pharmacological
targets. The search for ligands for orphan receptors and the identification of
novel signaling pathways has become a very active research field
(Gustafsson, 1999
;
Kliewer et al., 1999
).
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Canonical structure
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Nuclear receptors share a common structural organization. The N-terminal
region (A/B domain) is highly variable, and contains at least one
constitutionally active transactivation region (AF-1) and several autonomous
transactivation domains (AD); A/B domains are variable in length, from less
than 50 to more than 500 amino acids, and their 3D structure is not known. The
most conserved region is the DNA-binding domain (DBD, C domain), which notably
contains the P-box, a short motif responsible for DNA-binding specificity on
sequences typically containing the AGGTCA motif, and is involved in
dimerization of nuclear receptors. This dimerization includes homodimers as
well as heterodimers. The 3D structure of the DBD has been resolved for a
number of nuclear receptors and contains two highly conserved zinc-fingers
C-X2-C-X13-C-X2-C and C-X5-C-X9-C-X2-C the four cysteines of
each finger chelating one Zn2+ ion. The structure represented shows
the DBD of the human glucocorticoid receptor (GR) binding to DNA
(Hard et al., 1990
). Between
the DNA-binding and ligand-binding domains is a less conserved region (D
domain) that behaves as a flexible hinge between the C and E domains, and
contains the nuclear localization signal (NLS), which may overlap on the C
domain. The largest domain is the moderately conserved ligand-binding domain
(LBD, E domain), whose secondary structure of 12
-helixes is better
conserved than the primary sequence. The 3D structure has been determined for
several nuclear receptors (reviewed by
Moras and Gronemeyer, 1998
),
unliganded (apo) or liganded (holo), allowing much better understanding of the
mechanisms involved in ligand binding. We show the LBD of RXR
in apo
form (Bourguet et al., 1995
)
and in holo form with its natural ligand 9-cis retinoic acid
(Egea et al., 2000
) (figures
courtesy of Jean-Marie Wurtz, Institut de Génétique et de
Biologie Moléculaire et Cellulaire, Illkirch, France). The E domain is
responsible for many functions, mostly ligand induced, notably the AF-2
transactivation function, a strong dimerization interface, another NLS, and
often a repression function. Nuclear receptors may or may not contain a final
domain in the C-terminus of the E domain, the F domain, whose sequence is
extremely variable and whose structure and function are unknown.
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Diversity of nuclear receptors
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Nuclear receptors form a superfamily of phylogenetically related proteins,
with 21 genes in the complete genome of the fly Drosophila
melanogaster (Adams et al.,
2000
), 48 in humans
(Robinson-Rechavi et al.,
2001
) [but one more, FXRß, in the mouse
(Robinson-Rechavi and Laudet,
2003
)] and, unexpectedly, more than 270 genes in the nematode worm
Caenorhabditis elegans (Sluder et
al., 1999
). This diversity has been organized in a phylogeny-based
nomenclature (Nuclear Receptors
Nomenclature Committee, 1999
) of the form NRxyz, where
x is the sub-family, y is the group and z the gene.
In addition to nuclear receptors that have both DNA-binding and ligand-binding
domains, sub-family NR0 contains weird nuclear receptors that lack either of
these domains, and are not represented in the phylogenetic tree. They include
notably Knirps, KNRL and EGON (NR0A1, 2, 3) in Drosophila, and DAX1
and SHP (NR0B1, 2) in vertebrates.
The superfamily includes receptors for hydrophobic molecules such as
steroid hormones (e.g. estrogens, glucocorticoids, progesterone,
mineralocorticoids, androgens, vitamin D3, ecdysone, oxysterols and bile
acids), retinoic acids (all-trans and 9-cis isoforms), thyroid hormones, fatty
acids, leukotrienes and prostaglandins
(Escriva et al., 2000
;
Laudet and Gronemeyer, 2002
).
RXRs (USP in arthropods, indicated by a red dot in the phylogeny) play a
central role in dimerization of nuclear receptors, and we have indicated its
partners by a red star in the phylogenetic tree (for a review, see
Laudet and Gronemeyer, 2002
);
the stars with a question mark indicate the controversial description of
hetero-dimerization of COUP-TF with RXR, and the lack of information on
FXRß.
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Mode of action
|
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Nuclear receptors classically act in three steps (reviewed by
Laudet and Gronemeyer, 2002
):
repression, derepression and transcription activation. Repression is
characteristic of the apo-nuclear receptor, which recruits a corepressor
complex with histone deacetylase activity (HDAC; represented in the lower half
of the bottom-right inset). Derepression occurs following ligand binding,
which dissociates this complex and recruits a first coactivator complex, with
histone acetyltransferase (HAT) activity, resulting in chromatin
decondensation, which is believed to be necessary but not sufficient for
activation of the target gene. In the third step, the HAT complex dissociates
and a second coactivator complex is assembled (TRAP/DRIP/ARC), which is able
to establish contact with the basal transcription machinery, and thus results
in transcription activation of the target gene. This is of course a very
schematic view, and the precise order of events is still debated. It should
also be noted that this mechanism is not general, since some nuclear receptors
may act as activators without a ligand, whereas others are unable to interact
with the target gene promoter in the absence of ligand (the `repression'
step).
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Related articles in JCS:
- A guide to nuclear receptors
JCS 2003 116: 406.
[Full Text]