Nuclear receptor coregulators
Encyclopedia
Nuclear receptor coregulators are a class of transcription coregulators that have been shown to be involved in any aspect of signaling by any member of the nuclear receptor
superfamily. A comprehensive database of nuclear receptor coregulators can be found at the Nuclear Receptor Signaling Atlas website.
and including coactivators
and corepressors
. The study of nuclear receptors owed a debt to decades of historical endocrinology
and pathology
, and prior to their discovery there was a wealth of empirical evidence that suggested their existence. Coregulators, in contrast, have been the subject of a rapid accumulation of functional and mechanistic data which is yet to be consolidated into an integrated picture of their biological functions. While this article refers to the historical terms "coactivator" and "corepressor" it should be noted that this distinction is less clear than was at first thought, and it is now known that cell type, cell signaling state and promoter identity can influence the direction of action of any given coregulator.
Coregulators are often incorrectly referred to as cofactors
, which are small, non-protein molecules required by an enzyme for full activity, e.g. NAD+.
As far back as the early 1970s, receptor-associated nonhistone proteins were known to support the function of nuclear receptors. In the early 1990s, some investigators such as Keith Yamamoto had suggested a role for non-DNA nuclear acceptor molecules. A biochemical strategy designed in Myles Brown’s laboratory provided the first direct evidence of ligand-dependent recruitment by nuclear receptors of ancillary molecules.
The yeast two-hybrid protein-protein interaction assay led to the identification of an array of receptor-interacting factors in David Moore’s laboratory and RIP140
repressive protein was discovered in Malcolm Parker’s laboratory.
The stage was now set for the cloning of the coactivators. The first authentic, common nuclear receptor coactivator was steroid receptor coactivator 1, or SRC-1
, first cloned in Bert O’Malley’s laboratory. SRC-1 and two related proteins, GRIP-1
, cloned first by Michael Stallcup, and ACTR/p/CIP
, initially identified in Ron Evans and Geoff Rosenfeld’s lab, together make up the SRC family of coactivators. The SRC family is defined by the presence in the N-terminus of tandem PAS and beta-HLH motifs; a centrally-located domain which binds the coactivators CBP and p300
; and a C-terminal region which mediates interaction with the CARM-1
coactivator. Malcolm Parker’s laboratory was the first to show that a recurring structural feature of many coactivators is an alpha-helical
LXXLL motif
(a contiguous sequence of 5 amino acids where L = leucine and X = any amino acid), or nuclear receptor box, present from a single to several copies in many coactivators, which is implicated in their ligand-dependent recruitment by the receptor AF-2. The SRC coactivator family, for example, has a conserved cluster of NR boxes located in the central region of each member of the family.
Coactivators can be categorized based upon their varied functional properties. To name a few, classes of coactivators include:
Transcriptional repression by corepressors is in many ways conceptually comparable to the mediation of receptor transcriptional activation by coactivators, but has an opposite outcome. Recruitment of corepressors, generally occurring in the absence of ligand, depends on a critical conformation of the receptor AF-2 domain, as well as upon nuclear receptor box-like helical motifs in the corepressor. Moreover, corepressors themselves recruit ancillary enzyme activities which help to establish or maintain the repressive state at their target promoters.
Early cell transfection experiments had shown that discrete regions of certain receptors, such as thyroid hormone receptor, were sufficient to repress, or silence, reporter genes when fused to DNA-binding domains of heterologous transcription factors, suggesting that specific cellular factors – or corepressors - might bind to these regions and silence receptors in cells.
Again, using the yeast two-hybrid screen, two corepressors were isolated in rapid succession, nuclear receptor corepressor, or NCoR
, in Geoff Rosenfeld’s laboratory, and silencing mediator of retinoid and thyroid receptors, or SMRT
, by Ron Evans. Alignment of the two proteins indicated that they had a largely common domain structure, suggesting parallels in their mode of action.
Mitch Lazar’s group has shown that inactive nuclear receptors recruit corepressors in part through amphipathic helical peptides called CoRNR boxes, which are similar to the coactivator nuclear receptor boxes.
In addition to these structural analogies, corepressors and coactivators have common functional themes. The acetylation state of nucleosomes on a promoter is related to the rate of transcription of the gene. Histone acetylase coactivators increase the rate of acetylation, opening the nucleosome to transcription factors; histone deacetylases recruited by corepressors reverse this reaction, silencing transcription of the target gene. Other histone modifications have similar or opposite effects on transcription.
(TRAP220), Geoff Rosenfeld (NCoR), and Pierre Chambon (GRIP1) were able to delete, or knockout these genes in mice. These studies showed that coactivators were required for physiological and
developmental functions of steroid and thyroid hormones in living animals, and that corepressors too have crucial roles in the development of certain organs.
A spectrum of post-translational modifications is known to regulate the functional relationships between nuclear receptors, their coregulator complexes, and their target gene networks. Targeted, reversible enzymatic modifications such as acetylation, methylation phosphorylation and terminal modifications such as ubiquitination have been shown to have a variety of effects on coregulator function. Coregulators may be viewed as control interfaces for integrating multiple afferent stimuli into an appropriate cellular response. One possible scenario is that differential phosphorylation of coactivators may direct their combinatorial recruitment into different transcriptional complexes at distinct promoters in specific cells.
, Angelman Syndrome
and Von Gierke's disease. A comprehensive review of the role of coregulators in human disease has been published, which shows that over 165 of the known coregulators have been implicated in human pathologies.
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...
superfamily. A comprehensive database of nuclear receptor coregulators can be found at the Nuclear Receptor Signaling Atlas website.
Introduction
The ability of nuclear receptors to alternate between activation and repression in response to specific molecular cues, is now known to be attributable in large part to a diverse group of cellular factors, collectively termed coregulatorsTranscription coregulator
In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription are referred to as coactivators while those that...
and including coactivators
Coactivator (genetics)
A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
and corepressors
Corepressor (genetics)
In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
. The study of nuclear receptors owed a debt to decades of historical endocrinology
Endocrinology
Endocrinology is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions called hormones, the integration of developmental events such as proliferation, growth, and differentiation and the coordination of...
and pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
, and prior to their discovery there was a wealth of empirical evidence that suggested their existence. Coregulators, in contrast, have been the subject of a rapid accumulation of functional and mechanistic data which is yet to be consolidated into an integrated picture of their biological functions. While this article refers to the historical terms "coactivator" and "corepressor" it should be noted that this distinction is less clear than was at first thought, and it is now known that cell type, cell signaling state and promoter identity can influence the direction of action of any given coregulator.
Coregulators are often incorrectly referred to as cofactors
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
, which are small, non-protein molecules required by an enzyme for full activity, e.g. NAD+.
Coactivators
See also coactivatorsCoactivator (genetics)
A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
As far back as the early 1970s, receptor-associated nonhistone proteins were known to support the function of nuclear receptors. In the early 1990s, some investigators such as Keith Yamamoto had suggested a role for non-DNA nuclear acceptor molecules. A biochemical strategy designed in Myles Brown’s laboratory provided the first direct evidence of ligand-dependent recruitment by nuclear receptors of ancillary molecules.
The yeast two-hybrid protein-protein interaction assay led to the identification of an array of receptor-interacting factors in David Moore’s laboratory and RIP140
NRIP1
Nuclear receptor-interacting protein 1 is a protein that in humans is encoded by the NRIP1 gene.RIP140 has an important role in regulating lipid and glucose metabolism, and regulates gene expression in metabolic tissues including heart, skeletal muscle, and liver.Knockout mice that completely lack...
repressive protein was discovered in Malcolm Parker’s laboratory.
The stage was now set for the cloning of the coactivators. The first authentic, common nuclear receptor coactivator was steroid receptor coactivator 1, or SRC-1
Nuclear receptor coactivator 1
The nuclear receptor coactivator 1 is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity . NCOA1 is recruited to DNA promotion sites by ligand-activated nuclear receptors. NCOA1, in turn, acylates...
, first cloned in Bert O’Malley’s laboratory. SRC-1 and two related proteins, GRIP-1
Nuclear receptor coactivator 2
The nuclear receptor coactivator 2 is a transcriptional coregulatory protein which contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA2 is recruited to DNA promotion sites by ligand activated nuclear receptors. NCOA2 in turn acylates...
, cloned first by Michael Stallcup, and ACTR/p/CIP
Nuclear receptor coactivator 3
The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene. NCOA3 is also frequently called 'amplified in breast 1' , steroid receptor coactivator-3 , or thyroid hormone receptor activator molecule 1 .-Function:NCOA3 is a transcriptional...
, initially identified in Ron Evans and Geoff Rosenfeld’s lab, together make up the SRC family of coactivators. The SRC family is defined by the presence in the N-terminus of tandem PAS and beta-HLH motifs; a centrally-located domain which binds the coactivators CBP and p300
EP300
E1A binding protein p300 also known as EP300 or p300 is a protein that, in humans, is encoded by the EP300 gene. This protein regulates the activity of many genes in tissues throughout the body...
; and a C-terminal region which mediates interaction with the CARM-1
CARM1
CARM1 is an enzyme encoded by the gene found in human beings, as well as many other mammals. It has a polypeptide chain type that is 348 residues long, and is made up of alpha helices and beta sheets...
coactivator. Malcolm Parker’s laboratory was the first to show that a recurring structural feature of many coactivators is an alpha-helical
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
LXXLL motif
Structural motif
In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a supersecondary structure, which appears also in a variety of other molecules...
(a contiguous sequence of 5 amino acids where L = leucine and X = any amino acid), or nuclear receptor box, present from a single to several copies in many coactivators, which is implicated in their ligand-dependent recruitment by the receptor AF-2. The SRC coactivator family, for example, has a conserved cluster of NR boxes located in the central region of each member of the family.
Coactivators can be categorized based upon their varied functional properties. To name a few, classes of coactivators include:
- Acetyltransferases, such as members of the SRC family
- Ubiquitin ligaseUbiquitin ligaseA ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
s, such as E6-APUBE3AUbiquitin-protein ligase E3A also known as E6AP ubiquitin-protein ligase is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells... - ATP-coupled chromatin remodeling complexes, such as the SWI/SNFSWI/SNFSWI/SNF is a yeast nucleosome remodeling complex composed of several proteins – products of the SWI and SNF genes as well as several other polypeptides...
/BRG-1 complex - Protein methylaseMethylaseA methylase is an enzyme that attaches a methyl group to a molecule.These are found in prokaryotes and eukaryotes. Bacteria use methylase to differentiate between foreign genetic material and their own, thus protecting their DNA from their own immune system...
s, such as CARM-1 and PRMT-1PRMT1Protein arginine N-methyltransferase 1 is an enzyme that in humans is encoded by the PRMT1 gene.-Interactions:PRMT1 has been shown to interact with BTG2, KHDRBS1, ILF3, HNRPK, BTG1, HNRNPR, IFNAR1, FUS, DHX9 and SUPT5H.-Further reading:... - RNA transcripts, such as SRA
- Cell cycle regulators such as cdc 25BCDC25BM-phase inducer phosphatase 2 is an enzyme that in humans is encoded by the CDC25B gene.-Interactions:CDC25B has been shown to interact with MAPK14, Casein kinase 2, alpha 1, CHEK1, MELK, Estrogen receptor alpha, YWHAB, YWHAZ, YWHAH and YWHAE....
- RNA helicases such as p72
- And members of the TRAP/DRIP complex, which foster direct contact with components of the basal transcription machinery
Corepressors
See also corepressorsCorepressor (genetics)
In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
Transcriptional repression by corepressors is in many ways conceptually comparable to the mediation of receptor transcriptional activation by coactivators, but has an opposite outcome. Recruitment of corepressors, generally occurring in the absence of ligand, depends on a critical conformation of the receptor AF-2 domain, as well as upon nuclear receptor box-like helical motifs in the corepressor. Moreover, corepressors themselves recruit ancillary enzyme activities which help to establish or maintain the repressive state at their target promoters.
Early cell transfection experiments had shown that discrete regions of certain receptors, such as thyroid hormone receptor, were sufficient to repress, or silence, reporter genes when fused to DNA-binding domains of heterologous transcription factors, suggesting that specific cellular factors – or corepressors - might bind to these regions and silence receptors in cells.
Again, using the yeast two-hybrid screen, two corepressors were isolated in rapid succession, nuclear receptor corepressor, or NCoR
Nuclear receptor co-repressor 1
The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 is a protein that in humans is encoded by the NCOR1 gene....
, in Geoff Rosenfeld’s laboratory, and silencing mediator of retinoid and thyroid receptors, or SMRT
Nuclear receptor co-repressor 2
The nuclear receptor co-repressor 2 is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists nuclear receptors in the down regulation of target...
, by Ron Evans. Alignment of the two proteins indicated that they had a largely common domain structure, suggesting parallels in their mode of action.
Mitch Lazar’s group has shown that inactive nuclear receptors recruit corepressors in part through amphipathic helical peptides called CoRNR boxes, which are similar to the coactivator nuclear receptor boxes.
In addition to these structural analogies, corepressors and coactivators have common functional themes. The acetylation state of nucleosomes on a promoter is related to the rate of transcription of the gene. Histone acetylase coactivators increase the rate of acetylation, opening the nucleosome to transcription factors; histone deacetylases recruited by corepressors reverse this reaction, silencing transcription of the target gene. Other histone modifications have similar or opposite effects on transcription.
Biology of coregulators
The physiological role of SRC/p160s, CBP/p300 and other coactivators has been implied by knockout studies in mice of genes encoding these proteins. The effects of these deletions range from the profound effects on viability characteristic of TRAP220, CBP and p300, to the more subtle developmental and metabolic phenotypes associated with members of the SRC family. Using sequences from cloned coregulator genes, laboratories such as those led by Bert O’Malley (SRC-1), Bob RoederRobert G. Roeder
Robert G. Roeder is an American biologist. He is known as a pioneer in eukaryotic transcription. He is the recipient of the Gairdner Foundation International Award in 2000 and the Albert Lasker Award for Basic Medical Research in 2003...
(TRAP220), Geoff Rosenfeld (NCoR), and Pierre Chambon (GRIP1) were able to delete, or knockout these genes in mice. These studies showed that coactivators were required for physiological and
developmental functions of steroid and thyroid hormones in living animals, and that corepressors too have crucial roles in the development of certain organs.
Regulation of coregulator function
General model
Coactivators exist in large, modular complexes in the cell, and are known to participate in many different protein-protein interactions. A current model is that the composition of these complexes can become fluid, mixing and matching subunits to tailor the specific needs of different receptors, ligands or promoters. While spatiotemporal aspects of nuclear receptor and coregulator action remain poorly defined, a broad composite model of nuclear receptor action invokes corepressors as critical mediators of nuclear receptor silencing. In turn, a variety of coactivators are implicated in transcriptional activation by nuclear receptors, including SWI/SNF chromatin remodeling machines, SRC/p160s and TRAP/DRIP. The model accommodates the ability of membrane G protein coupled signaling pathways and tyrosine receptor signaling to cross-talk with coactivator and corepressor functions at the transcriptional level.Coregulators and human disease
With the well-documented role of nuclear receptor coregulators in a variety of molecular functions within the cell, it should come as no surprise that evidence implicates them in a wide variety of diseases states, including cancer, metabolic syndromes (obesity, diabetes) and heritable syndromes such as Rubinstein-Taybi SyndromeRubinstein-Taybi syndrome
Rubinstein-Taybi Syndrome , also known as broad thumb-hallux syndrome or Rubinstein syndrome, is a condition characterized by short stature, moderate to severe learning difficulties, distinctive facial features, and broad thumbs and first toes. Other features of the disorder vary among affected...
, Angelman Syndrome
Angelman syndrome
Angelman syndrome is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements , frequent laughter or smiling, and usually a happy demeanor....
and Von Gierke's disease. A comprehensive review of the role of coregulators in human disease has been published, which shows that over 165 of the known coregulators have been implicated in human pathologies.