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Ligand binding and nuclear

receptor evolution

Hector Escriva, Franck Delaunay, and Vincent Laudet*

Summary

Nuclear receptors form a superfamily of ligand-activated

transcription factors that regulate various physiological

functions, from development to homeostasis, in me-

tazoans. The superfamily contains not only receptors

for known ligands but also a large number of so-called

orphan receptors for which ligands do not exist or have

not been identified. The evolution of ligand-binding

capacity of nuclear receptors may involve either sec-

ondary loss in orphan receptors, or evolutionary acqu-

isition of ligand-binding capacity in liganded receptors.

In this review, we present arguments from phylogenetic,

functional and structural studies that support the

hypothesis that there have been several independent

gains of ligand-binding ability of nuclear receptors

during metazoan evolution. BioEssays 22:717±727,

2000. ß 2000 John Wiley & Sons, Inc.

Introduction

Nuclear hormone receptors (NRs) are one of the most

abundant classes of transcriptional regulators in metazoans,

in which they regulate functions as diverse as reproduction,

differentiation, development, metabolism, metamorphosis

and homeostasis. NRs function as ligand-activated transcrip-

tion factors, thus providing a direct link between signalling

molecules that control these processes and transcriptional

responses.

(1)

The basic concept of a NR signalling pathway

involves production of the signal (endocrine, paracrine,

autocrine or even intracrine), its transport to peripheral

organs, binding of the ligand to the receptor, and transcrip-

tional activation of the receptor.

NRs share a common structural organization with a

central, well-conserved DNA-binding domain (DBD, also

termed C domain), a variable N-terminal region (A/B domain)

a non-conserved hinge (D domain) and a carboxy-terminus,

moderately conserved ligand-binding domain (LBD, E

domain) (Fig. 1).

NRs are phylogenetically related proteins clustered into a

large superfamily, including receptors for hydrophobic

molecules such as steroid hormones (estrogens, glucocorti-

coids, progesterone, mineralocorticoids, androgens, vitamin

D, ecdysone, oxysterols, bile acids etc), retinoic acids (all-

trans and 9-cis isoforms), thyroid hormones, fatty acids,

leukotrienes and protaglandins (Fig. 2). In addition, a number

of receptors, for which ligands either do not exist or still have

to be identified have been described and are referred to as

orphan receptors. NRs are promising pharmacological

targets as they bind small molecules, which can be easily

modified by drug design, and control functions associated

with major pathologies (cancer, osteoporosis, diabetes, etc).

The development of synthetic ligands for ER, RAR and

PPARg has, for instance, already led to pharmacological

applications for cancer and type 2 diabetes. Because of

these important therapeutic applications, the search of

ligands for orphan receptors and the identification of novel

signalling pathways has become a very active research

field.

(2)

The structural diversity of the ligands contrasts with the

conservation and mode of action of their receptors. This, and

the large number of orphan receptors, have prompted much

speculation on the origins of this signalling pathway. A

classical view suggests that orphan receptors have evolved

as liganded molecules, which through gene duplication

reached the present day diversity.

(3)

According to this model,

orphan receptors would have lost their ability to bind ligands

recently in evolution. We recently suggested an alternative

hypothesis, in which ligand binding was acquired during NRs

evolution.

(4)

The ancestral receptor would have been an

orphan receptor and the various liganded receptors have

gained ligand recognition independently during evolution. In

BioEssays 22:717±727, ß 2000 John Wiley & Sons, Inc. BioEssays 22.8 717

Ecole Normale Supe

rieure de Lyon, Lyon, France.

Funding agencies: EMBO, Fondation pour la Recherche Me

dicale,

ARC, LNCC, CNRS and MENRT.

*Correspondence to: Vincent Laudet, UMR 5665 du CNRS, Ecole

Normale Supe

rieure de Lyon, 46 alle

e d'Italie, 69364 Lyon Cedex 07,

France. E-mail: Vincent.Laudet@ens-lyon.fr

Abbreviations: AF2-AD, activation function 2-autonomous domain,

AR, androgen receptor, CARb, constitutive activated receptor b, DBD,

DNA-binding domain, DR, direct repeat, EcR, ecdysone receptor, ER,

estrogen receptor, ERKO, estrogen receptor knock out, ERR,

estrogen related receptor, FXR, farnesol X receptor, GCNF, germ

cell nuclear factor, GR, glucocorticoid receptor, HRE, hormone

response element, LBD, ligand-binding domain, LXR, liver X receptor,

MR, mineralocorticoid receptor, NGFIB, nerve growth factor induced

gene B, NR, nuclear receptor, PPAR, peroxisome proliferating

activated receptor, PR, progesterone receptor, PRKO, progesterone

receptor knock out, PXR, pregnane X receptor, RAR, retinoic acid

receptor, ROR, retinoic and related orphan receptor, RXR, retinoic X

receptor, SF1, steroidogenic factor 1, SRC-1, steroid receptor

coregulator 1, T3, triiodothyronine, TR, thyroid hormone receptor,

USP, ultraspiracle, VDR, vitamin D receptor.

Review articles

this review, we discuss arguments from phylogenetic,

functional and structural studies that support a recent gain

of ligand-binding ability in classical receptors, rather than a

loss of ligand binding in orphan receptors during metazoan

evolution.

How to turn on a NR?

NRs bind as homodimers or heterodimers to specific DNA

sequences, termed hormone response elements (HRE),

which are most often formed by a repetition of the core

consensus motif PuGGTCA.

(1)

For example, steroid recep-

tors bind as homodimers to HREs containing two core motifs

separated by 1±3 nucleotides and organised as palin-

dromes. A number of receptors, including retinoic acid

receptors (RARs), thyroid hormone receptors (TRs), and

some orphan receptors (NGFIB), heterodimerize with re-

tinoid X receptors (RXRs) and bind to direct repeats (DR) of

the core motif. The spacing between the two halves of the DR

dictates the type of heterodimer that will bind.

(1)

For example,

a DR separated by five nucleotides (DR5) will be most often

recognised by an RXR-RAR heterodimer, whereas a DR4

will be bound by an RXR-TR heterodimer. Some receptors,

such as the SF1, ROR or Rev-erb orphan receptors, can

bind to DNA as monomers through a single core sequence.

In this case, an A/T-rich region 5

to the core element

governs the binding specificity. At present, only orphan

receptors are known to bind as monomers to these half sites.

It was recently shown that some orphan receptors (e.g. ERR-

1, GCNF) can also bind a single core motif as dimers.

(5,6)

Many NRs are transcriptional silencers in the absence of

ligand (apo-receptor) as a result of interaction with inter-

mediary factors known as co-repressors.

(7,8)

Determination

of the three-dimensional structure of NRs has shown that the

LBD region is structured as a three-layered a-helical anti-

parallel sandwich of 12 helices forming an hydrophobic

pocket. Upon ligand binding (holo-receptor), the ligand

makes different contacts with amino-acid residues, promot-

ing a conformational change that closes the ``lid'' (helix 12,

H12) on the pocket. Thus the activation domain within the

H12 (AF2-AD) is able to interact with co-activators and

promotes transcription of target genes.

(9±12)

The conforma-

tional change of the LBD upon ligand binding is therefore

necessary for the transactivation function of NRs. It is

believed that co-repressors and co-activators modulate

transcription at least in part by modifying the status of

histone acetylation in chromatin. An opposite mode of action

was demonstrated for the orphan receptor CARb, for which

binding of steroid-like compounds (androstanol) was shown

to repress its transcriptional activity.

(13)

In the apo-conforma-

tion, CARb interacts with co-activators such as SRC-1,

whereas androstanol binding reverses this interaction.

In summary, a NR ligand can be defined as a small

hydrophobic molecule that directly binds to the LBD and

promotes a structural rearrangement allowing the AF2-AD

region to interact with transcriptional coregulators (co-

activators, co-repressors) that will connect the NR to the

basic transcriptional machinery, resulting in the transcrip-

tional stimulation/silencing of target genes.

Evolution of NRs

Alignment of the well-conserved DBD and LBD, and

phylogenetic analysis has resulted in an evolutionary tree

Figure 1. Structure of an archetypal nuclear hor-

mone receptor. The two conserved domains, C and

E, are boxed and their main functions are indicated.

AF-1 and AF-2AD, located, respectively, in N and C

termini are the trans-activation domains. NLS is the

nuclear localization signal.

Figure 2. Chemical structure of endogenous known nuclear receptor ligands and activators. Their respective K

or EC

are indicated.

Binding/activation by palmitoyl-CoA and 25-hydroxycholesterol to/of HNF4 and SF1 receptors respectively have not been reproduced.

The name of each group (i. e. subfamily name) according to the recent nomenclature

(18)

is indicated below the chemical name (see

Fig. 3).

Review articles

718 BioEssays 22.8

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