The Nuclear Receptor Superfamily

Evidence for the physiological importance of the nuclear hormone receptors lies in the ancient evolutionary origin of the superfamily. The high degree of sequence similarity between vertebrate and invertebrate receptors indicates that these receptors evolved before this branch in the evolutionary tree.85 The 48 members of the nuclear hormone receptor family found in humans are shown in Table 6.1. With a few exceptions (see below), nuclear receptors share a common structural organization (Fig. 6.1). A ligand-independent activation function (AF-1) is located in the amino terminal region of most receptors. The core DNA binding domain contains two highly conserved zinc finger motifs responsible for the recognition of DNA sequences known as hormone response elements (HRE).15,84 The nuclear localization signal of receptors that mostly localize in the nucleus can be found in this region. The DNA binding domain is connected to the ligand binding domain by a hinge region, which provides flexibility

J.L. Holtzman (ed.), Atherosclerosis and Oxidant Stress: A New Perspective. © Springer 2007

Table 6.1 Nuclear hormone receptor superfamily

Orphan receptors

Adopted receptors

Identified ligands

SF-1

ER alpha, beta

Estrogen

SHP

AR

Testosterone

TLX

PR

Progesterone

PNR

GR

Glucocorticoid

LRH-1

MR

Mineralocorticoid

DAX-1

VDR

Vitamin D

GCNF

RAR alpha, beta,

Retinoic acid

gamma

HNF-4 alpha, gamma

TR alpha, beta

Thyroid hormone

TR 2,4

FXR

Bile acids

ERR alpha, beta,

CAR

Xenobiotics

gamma

Rev-erb alpha, beta

LXR alpha, beta

Oxysterols

ROR alpha, beta,

PXR

Xenobiotics

gamma

NGFI-B alpha, beta,

RXR

9-cis-retinoic acid

gamma

COUP-TF alpha, beta,

PPAR alpha, delta/beta,

Fatty acids

gamma

gamma

Fig. 6.1 Nuclear hormone receptor structure. Top: schematic of NHR gene depicting different domains. Bottom: Schematic of NHR protein and the hexamer of DNA that it recognizes between these two domains. The ligand binding domain encompasses a large portion of the c-terminal region of the protein and is responsible for many functions other than ligand binding. The ligand-dependent activation function (AF-2) is at the carboxyl terminus; also contained with- in this domain is the dimeriza-tion interface and the nuclear localization signal, for receptors that localize to the cytoplasm in the inactive state.

The first nuclear hormone receptors were identified by endocrinologists searching for the receptors through which steroid hormones elicit their effects. Due to the homology within the receptor superfamily, sequencing the glucocorti-coid receptor and estrogen receptor opened the door for discovery of other classic steroid and nonsteroid hormone receptors. The rest of the family members were subsequently identified using the highly conserved DNA binding domain in low stringency hybridization screenings of cDNA libraries, without prior knowledge of the receptors' functions or ligands. Receptors that could not be assigned hormones were called orphan receptors. Over the past two decades since the primary sequences were first discovered, some of the receptors have been "adopted" by ligands. The identified ligands were not novel hormones as was originally assumed, but metabolites of nutrients such as cholesterol and fatty acids, leading to the classification of these adopted receptors as metabolic sensors.26 Many receptors remain orphans; although they all contain a ligand binding domain it is possible that some of these receptors may be regulated in a solely ligand-independent manner.19,186

The subfamilies of nuclear hormone receptors can be classified based on their dimerization partners and specific HRE recognized by the receptors.112,163 This classification method groups the steroid hormones in class I and the metabolic sensors in class II, while the orphans are in classes III and IV (Table 6.2). As metabolic sensors, the class II receptors are involved in metabolic pathways relevant to metabolic diseases and will be discussed in the most detail. However members of the other classes also regulate metabolism and will be discussed as examples for their class. In this text the common receptor names are used. However all the receptors have been given official names, which split the receptors into seven groups, NR0 through NR6 based on their DNA binding domain sequence.126 The receptors are then further divided into subfamilies denoted by a letter and isotype denoted by a number; for example, the official name of peroxisome proliferator activated receptor (PPAR) gamma is NR1B3, where B refers to the PPAR subfamily, and 3 refers to the gamma isotype.

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