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RAR-related orphan receptor alpha (RORα), also known as NR1F1 (nuclear receptor subfamily 1, group F, member 1) is a
nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the ex ...
that in humans is encoded by the ''RORA''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
RORα participates in the transcriptional regulation of some genes involved in
circadian rhythm
A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., Endogeny (biology), endogenous) and responds to the env ...
.
In mice, RORα is essential for development of
cerebellum
The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...
through direct regulation of genes expressed in Purkinje cells. It also plays an essential role in the development of
type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient. In addition, although present in normal numbers, the
ILC3 and Th17 cells from RORα deficient mice are defective for
cytokine
Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling.
Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
production.
Discovery
The first three-human isoforms of RORα were initially
cloned
Cloning is the process of producing individual organisms with identical genomes, either by natural or artificial means. In nature, some organisms produce clones through asexual reproduction; this reproduction of an organism by itself without ...
and characterized as nuclear receptors in 1994 by Giguère and colleagues, when their structure and function were first studied.
In the early 2000s, various studies demonstrated that RORα displays rhythmic patterns of expression in a circadian cycle in the
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
,
kidney
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
,
retina
The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...
, and
lung
The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
.
Of interest, it was around this time that RORα abundance was found to be circadian in the mammalian
suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei (SCN) is a small region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for regulating sleep cycles in animals. Reception of light inputs from photosensitive r ...
.
RORα is necessary for normal
circadian rhythm
A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., Endogeny (biology), endogenous) and responds to the env ...
s in
mice
A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
,
demonstrating its importance in
chronobiology
Chronobiology is a field of biology that examines timing processes, including periodic (cyclic) phenomena in living organisms, such as their adaptation to solar- and lunar-related rhythms. These cycles are known as biological rhythms. Chron ...
.
Structure
The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors.
In humans, 4
isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
of RORα have been identified, which are generated via alternative
splicing and
promoter usage, and exhibit differential tissue-specific expression. The
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
structure of RORα consists of four canonical functional groups: an
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
(A/B) domain, a
DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
-binding
domain
A domain is a geographic area controlled by a single person or organization. Domain may also refer to:
Law and human geography
* Demesne, in English common law and other Medieval European contexts, lands directly managed by their holder rather ...
containing two
zinc finger
A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) which stabilizes the fold. The term ''zinc finger'' was originally coined to describe the finger-like appearance of a ...
s, a hinge domain, and a
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...
ligand
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
-binding domain. Within the ROR family, the DNA-binding domain is highly conserved, and the ligand-binding domain is only moderately conserved.
Different isoforms of RORα have different binding specificities and strengths of
transcriptional activity.
Regulation of circadian rhythm
The core
mammal
A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...
ian circadian clock is a
negative feedback
Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused ...
loop which consists of
Per1/Per2,
Cry1/Cry2,
Bmal1
Basic helix-loop-helix ARNT-like protein 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), or brain and muscle ARNT-like 1 is a protein that in humans is encoded by the ''BMAL1'' gene on chromosome 11, region p15.3. It's ...
, and
Clock
A clock or chronometer is a device that measures and displays time. The clock is one of the oldest Invention, human inventions, meeting the need to measure intervals of time shorter than the natural units such as the day, the lunar month, a ...
.
This feedback loop is stabilized through another loop involving the transcriptional regulation of ''Bmal1''.
Transactivation In the context of gene regulation: transactivation is the increased rate of gene expression triggered either by biological processes or by artificial means, through the expression of an intermediate transactivator protein.
In the context of recep ...
of ''Bmal1'' is regulated through the upstream ROR/REV-ERB
Response Element ''Response elements'' are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes.
Under conditions of stress, a transcription activator protein bi ...
(RRE) in the ''Bmal1'' promoter, to which RORα and
REV-ERBα bind.
This stabilizing regulatory loop itself is induced by the Bmal1/Clock
heterodimer
In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...
, which induces transcription of ''RORα'' and ''REV-ERBα''.
RORα, which activates transcription of ''Bmal1'', and REV-ERBα, which represses transcription of ''Bmal1'', compete to bind to the RRE.
This feedback loop regulating the expression of ''Bmal1'' is thought to stabilize the core clock mechanism, helping to buffer it against changes in the
environment.
Mechanism
Specific association with ROR elements (RORE) in regulatory regions is necessary for RORα's function as a transcriptional activator.
[cardiovascular
In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...]
endocrinology
Endocrinology (from ''endocrine system, endocrine'' + ''wikt:-logy#Suffix, -ology'') is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions known as hormones. It is also concerned with the ...
"> RORα achieves this by specific binding to a consensus core motif in RORE, RGGTCA. This interaction is possible through the association of RORα's first zinc finger with the core motif in the major groove, the P-box, and the association of its C-terminal extension with the AT-rich region in the 5’ region of RORE.
Homology
RORα,
RORβ, and
RORγ are all transcriptional activators recognizing ROR-response elements.
ROR-alpha is expressed in a variety of cell types and is involved in regulating several aspects of development,
inflammatory responses, and
lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...
development.
The RORα isoforms (RORα1 through RORα3) arise via alternative RNA processing, with RORα2 and RORα3 sharing an amino-terminal region different from RORα1.
In contrast to RORα, RORβ is expressed in
Central Nervous System
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
(CNS) tissues involved in processing sensory information and in generating
circadian rhythms
A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., endogenous) and responds to the environment (is entrai ...
while RORγ is critical in
lymph node
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
organogenesis
Organogenesis is the phase of embryonic development that starts at the end of gastrulation and continues until birth. During organogenesis, the three germ layers formed from gastrulation (the ectoderm, endoderm, and mesoderm) form the internal org ...
and
thymopoeisis.
The DNA-binding domains of the DHR3 orphan receptor in ''Drosophila'' shows especially close
homology within
amino
In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...
and
carboxy regions adjacent to the second zinc finger region in RORα, suggesting that this group of
residues is important for the proteins' functionalities.
PDP1 and VRI in ''Drosophila'' regulate circadian rhythm's by competing for the same binding site, the VP box, similarly to how ROR and REV-ERB competitively bind to RRE.
PDP1 and VRI constitute a
feedback loop
Feedback occurs when outputs of a system are routed back as inputs as part of a chain of cause and effect that forms a circuit or loop. The system can then be said to ''feed back'' into itself. The notion of cause-and-effect has to be handle ...
and are functional homologs of ROR and REV-ERB in mammals.
Direct orthologs of this gene have been identified in mice and humans.
Human
cytochrome c pseudogene HC2 and RORα share overlapping genomic organization with the HC2 pseudogene located within the RORα2 transcription unit. The nucleotide and deduced amino acid sequences of cytochrome c-processed pseudogene are on the
sense
A sense is a biological system used by an organism for sensation, the process of gathering information about the surroundings through the detection of Stimulus (physiology), stimuli. Although, in some cultures, five human senses were traditio ...
strand while those of the RORα2 amino-terminal exon are on the antisense strand.
Interactions
*DNA: RORα binds to the P-box of the RORE.
*
Co-activators:
**
SRC-1,
CBP,
p300, TRIP-l,
TRIP-230, transcription intermediary protein-1 (
TIF-1), peroxisome proliferator-binding protein (PBP), and
GRIP-1 physically interact with RORα.
***LXXLL motif: ROR interacts with SRC-1, GRIP-l, CBP, and p300 via the
LXXLL (L=Leucine, X=any amino acid) motifs on these proteins.
*
Ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...
ation: RORα is targeted for the
proteasome
Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...
by ubiquitination. A
co-repressor, Hairless, stabilizes RORα by protecting it from this process, which also represses RORα.
*
Sumoylation
In molecular biology, SUMO (Small Ubiquitin-like Modifier) proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation (pronounced ...
: UBE21/UBC9: Ubiquitin-conjugating enzyme I interacts with RORs, but its effect is not yet known.
*
Phosphorylation
In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols:
:
This equation can be writ ...
:
**Phosphorylation of RORα1, which inhibits its transcriptional activity, is induced by
Protein Kinase C
In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
.
**
ERK2:
Extracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
signal-regulated kinase-2 also phosphorylates RORα.
*
ATXN1: ATXN1 and RORα form part of a protein complex in
Purkinje cells
Purkinje cells or Purkinje neurons, named for Czech physiologist Jan Evangelista Purkyně who identified them in 1837, are a unique type of prominent, large neuron located in the cerebellar cortex of the brain. With their flask-shaped cell bo ...
.
*
FOXP3
FOXP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of r ...
: FOXP3 directly represses the transcriptional activity of RORs.
*
NME1
Nucleoside diphosphate kinase A is an enzyme that in humans is encoded by the ''NME1'' gene. It is thought to be a metastasis suppressor.
Function
This gene (NME1) was identified because of its reduced mRNA transcript levels in highly metast ...
: ROR has been shown to specifically interact with NME1.
*
NM23-2: NM23-2 is a nucleoside diphosphate
kinase
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
involved in organogenesis and differentiation.
*
NM23-1: NM23-1 is the product of a tumor
metastasis suppressor candidate gene.
As a drug target
Because RORα and REV-ERBα are nuclear receptors that share the same target genes and are involved in processes that regulate
metabolism
Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
,
development
Development or developing may refer to:
Arts
*Development (music), the process by which thematic material is reshaped
* Photographic development
*Filmmaking, development phase, including finance and budgeting
* Development hell, when a proje ...
,
immunity
Immunity may refer to:
Medicine
* Immunity (medical), resistance of an organism to infection or disease
* ''Immunity'' (journal), a scientific journal published by Cell Press
Biology
* Immune system
Engineering
* Radiofrequence immunity ...
, and circadian rhythm, they show potential as
drug targets. Synthetic ligands have a variety of potential therapeutic uses, and can be used to treat diseases such as
diabetes
Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
,
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
,
autoimmunity
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease ...
, and
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
. T0901317 and SR1001, two synthetic ligands, have been found to be RORα and
RORγ inverse agonist
In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.
A neutral antagonist has no activity in the absence of an agonist or inverse agon ...
s that suppress
reporter
A journalist is a person who gathers information in the form of text, audio or pictures, processes it into a newsworthy form and disseminates it to the public. This is called journalism.
Roles
Journalists can work in broadcast, print, advertis ...
activity and have been shown to delay onset and clinical severity of
multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
and other
Th17
T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. Howe ...
cell-mediated autoimmune diseases. SR1078 has been discovered as a RORα and RORγ agonist that increases the expression of G6PC and FGF21, yielding the therapeutic potential to treat
obesity
Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
and diabetes as well as cancer of the
breast
The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...
,
ovaries
The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are endocr ...
, and
prostate
The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
. SR3335 has also been discovered as a RORα inverse agonist.
See also
*
RAR-related orphan receptor
*
REV-ERBα
*
Aromatase deficiency
References
Further reading
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External links
*
{{Receptor/signaling modulators
Intracellular receptors
Transcription factors