Nuclear receptor related 1 protein
Encyclopedia
The Nuclear receptor related 1 protein (NURR1) also known as NR4A2 (nuclear receptor subfamily 4, group A, member 2) is a protein
that in humans is encoded by the NR4A2 gene
. NURR1 is a member of the nuclear receptor
family of intracellular
transcription factor
s.
NURR1 plays a key role in the maintenance of the dopaminergic
system of the brain. Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including Parkinson's disease
, schizophrenia
, and manic depression. Misregulation of this gene may be associated with rheumatoid arthritis
. Four transcript variants encoding four distinct isoforms have been identified for this gene. Additional alternate splice variants may exist, but their full length nature has not been determined.
(TH) expression, which eventually leads to differentiation into dopaminergic neurons. Nurr1 has been demonstrated to induce differentiation in CNS precursor cells in vitro but they require additional factors for these induced dopaminergic to reach full maturity. This is promising for generation of dopaminergic neurons for Parkinson’s disease research, yet implantation of these induced cells as therapy treatments, has had limited results.
with:
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the NR4A2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. NURR1 is a member of the nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
family of intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s.
NURR1 plays a key role in the maintenance of the dopaminergic
Dopaminergic
Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
system of the brain. Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, and manic depression. Misregulation of this gene may be associated with rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
. Four transcript variants encoding four distinct isoforms have been identified for this gene. Additional alternate splice variants may exist, but their full length nature has not been determined.
Nurr1 and Inflammation
Research has been conducted on Nurr1’s role in inflammation, and may provide important information in treating disorders caused by dopaminergic neuron disease. Inflammation in the CNS can result from activated microglia (macrophage analogs for the central nervous system) and other pro-inflammatory factors, such as bacterial lipopolysaccharide (LPS). LPS binds to toll like receptors (TLR), which induces inflammatory gene expression by promoting signal dependant transcription factors. To determine which cells are dopaminegenic, experiments measure the enzyme tyrosine hydroxylase, since this enzyme is need to synthesize dopamine. It has been shown that Nurr1 protects dopamengeric neurons from LPS induced inflammation, by reducing the inflammatory gene expression in microglial and asterocytes. When a short hairpin for Nurr1 was expressed in microglial and astrocytes, they produced inflammatory mediators, such as TNFa, NO synthase and ILβ. Supporting the conclusion that reduced Nurr1 promotes inflammation and leads to cell death of dopamenergetic neurons. Nurr1 interacts with a transcription factor complex NF-κB-p65 on the inflammatory gene promoters. However, for Nurr1 is dependant on other factors to be able to participate in these interactions. Nurr1 needs to be sumoylated and its co-regulating factor; glycogen synthase kinase 3 needs to be phorphorylated for these interactions to occur. Sumolyated Nurr1 recruits CoREST, a complex made of several proteins that assembles chromatin-modifying enzymes. The Nurr1/CoREST complex inhibits transcription of inflammatory genes.Structure
One investigation conducted research on the structure and found that Nurr1 does not contain a ligand binding cavity but an patch filled with hydrophobic side chains. Non-polar amino acid residues of Nurr1’s co-regulators, SMRT and NCoR, bind to this hydrophobic patch. Analysis of tertiary structure has shown that the binding surface of the ligand-binding domain is located on the grooves of the 11th and 12th alpha helices. This study also found essential structural components of this hydrophobic patch, to be the three amino acids residues, F574, F592, L593; mutation of any these three inhibits LBD activity.Applications
Nurr1 induces tyrosine hydroxylaseTyrosine hydroxylase
Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to dihydroxyphenylalanine . It does so using tetrahydrobiopterin as a coenzyme. DOPA is a precursor for dopamine, which, in turn, is a precursor for norepinephrine ...
(TH) expression, which eventually leads to differentiation into dopaminergic neurons. Nurr1 has been demonstrated to induce differentiation in CNS precursor cells in vitro but they require additional factors for these induced dopaminergic to reach full maturity. This is promising for generation of dopaminergic neurons for Parkinson’s disease research, yet implantation of these induced cells as therapy treatments, has had limited results.
Interactions
Nuclear receptor related 1 protein has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- Retinoic acid receptor alphaRetinoic acid receptor alphaRetinoic acid receptor alpha , also known as NR1B1 is a nuclear receptor that in humans is encoded by the RARA gene.- Function :...
- Retinoic acid receptor betaRetinoic acid receptor betaRetinoic acid receptor beta , also known as NR1B2 is a nuclear receptor that in humans is encoded by the RARB gene.- Function :...
.