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P35398

- RORA_HUMAN

UniProt

P35398 - RORA_HUMAN

Protein

Nuclear receptor ROR-alpha

Gene

RORA

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 152 (01 Oct 2014)
      Sequence version 2 (16 Apr 2014)
      Previous versions | rss
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    Functioni

    Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development, regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium-mediated signal transduction. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. May suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA-binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is implicated in the lineage specification of uncommitted CD4+ T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti-inflammatory role by inducing CHUK expression and inhibiting NF-kappa-B signaling.17 Publications

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    DNA bindingi73 – 13866Nuclear receptorPROSITE-ProRule annotationAdd
    BLAST
    Zinc fingeri73 – 9321NR C4-typePROSITE-ProRule annotationAdd
    BLAST
    Zinc fingeri109 – 13325NR C4-typePROSITE-ProRule annotationAdd
    BLAST

    GO - Molecular functioni

    1. direct ligand regulated sequence-specific DNA binding transcription factor activity Source: UniProtKB
    2. DNA binding Source: UniProtKB
    3. ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity Source: InterPro
    4. oxysterol binding Source: UniProtKB
    5. protein binding Source: UniProtKB
    6. sequence-specific DNA binding Source: UniProtKB
    7. sequence-specific DNA binding transcription factor activity Source: UniProtKB
    8. steroid hormone receptor activity Source: InterPro
    9. transcription coactivator binding Source: UniProtKB
    10. transcription corepressor binding Source: UniProtKB
    11. transcription factor binding Source: UniProtKB
    12. zinc ion binding Source: InterPro

    GO - Biological processi

    1. angiogenesis Source: UniProtKB
    2. cellular response to hypoxia Source: UniProtKB
    3. cellular response to sterol Source: UniProtKB
    4. cerebellar granule cell precursor proliferation Source: UniProtKB
    5. cerebellar Purkinje cell differentiation Source: Ensembl
    6. cGMP metabolic process Source: Ensembl
    7. circadian regulation of gene expression Source: UniProtKB
    8. gene expression Source: Reactome
    9. intracellular receptor signaling pathway Source: UniProtKB
    10. muscle cell differentiation Source: UniProtKB
    11. negative regulation of fat cell differentiation Source: UniProtKB
    12. negative regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
    13. negative regulation of inflammatory response Source: UniProtKB
    14. nitric oxide biosynthetic process Source: Ensembl
    15. positive regulation of circadian rhythm Source: UniProtKB
    16. positive regulation of transcription, DNA-templated Source: UniProtKB
    17. positive regulation of transcription from RNA polymerase II promoter Source: MGI
    18. positive regulation vascular endothelial growth factor production Source: UniProtKB
    19. regulation of cholesterol homeostasis Source: UniProtKB
    20. regulation of glucose metabolic process Source: UniProtKB
    21. regulation of macrophage activation Source: Ensembl
    22. regulation of smoothened signaling pathway Source: UniProtKB
    23. regulation of steroid metabolic process Source: UniProtKB
    24. regulation of transcription, DNA-templated Source: UniProtKB
    25. regulation of transcription involved in cell fate commitment Source: UniProtKB
    26. T-helper 17 cell differentiation Source: UniProtKB
    27. transcription initiation from RNA polymerase II promoter Source: Reactome
    28. triglyceride homeostasis Source: UniProtKB
    29. xenobiotic metabolic process Source: UniProtKB

    Keywords - Molecular functioni

    Activator, Receptor

    Keywords - Biological processi

    Biological rhythms, Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding, Metal-binding, Zinc

    Enzyme and pathway databases

    ReactomeiREACT_111118. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
    REACT_116145. PPARA activates gene expression.
    REACT_118659. RORA activates circadian gene expression.
    REACT_118789. REV-ERBA represses gene expression.
    REACT_15525. Nuclear Receptor transcription pathway.
    REACT_24941. Circadian Clock.
    SignaLinkiP35398.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Nuclear receptor ROR-alpha
    Alternative name(s):
    Nuclear receptor RZR-alpha
    Nuclear receptor subfamily 1 group F member 1
    RAR-related orphan receptor A
    Retinoid-related orphan receptor-alpha
    Gene namesi
    Name:RORA
    Synonyms:NR1F1, RZRA
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 15

    Organism-specific databases

    HGNCiHGNC:10258. RORA.

    Subcellular locationi

    Nucleus 2 PublicationsPROSITE-ProRule annotation

    GO - Cellular componenti

    1. nucleoplasm Source: Reactome
    2. nucleus Source: UniProtKB

    Keywords - Cellular componenti

    Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi183 – 1831T → A: Greatly increased transcriptional activity. Decrease in repression by NR1D1. 1 Publication
    Mutagenesisi183 – 1831T → D or E: Some increase in transcriptional activity. No change in repression by NR1D1. 1 Publication
    Mutagenesisi183 – 1831T → R: Attenuates transcriptional activity. 1 Publication
    Mutagenesisi183 – 1831T → V or I: Some increase in transcriptional activity. 1 Publication
    Mutagenesisi240 – 2401K → R: Loss of sumoylation. 1 Publication
    Mutagenesisi288 – 2881C → Q: Less effect on transcriptional activity with cholesterol sulfate as substrate as compared to cholesterol as substrate. 1 Publication
    Mutagenesisi323 – 3231C → L: About 60% loss of transcriptional activity. 2 Publications
    Mutagenesisi330 – 3301A → L: About 80% loss of transcriptional activity. 2 Publications
    Mutagenesisi335 – 3351V → R: Strongly decreases interaction with NCOA2 and MED1. 1 Publication
    Mutagenesisi339 – 3391K → A: Complete loss of transcriptional activity; when associated with A-507. 1 Publication
    Mutagenesisi357 – 3571K → A: Increased transcriptional activity. No effect on protein degradation. 1 Publication
    Mutagenesisi361 – 3611L → F: Small reduction in transcriptional activity. No protein degradation. 1 Publication
    Mutagenesisi364 – 3641V → G: Greatly reduced transcriptional activity. Protects from protein degradation. 1 Publication
    Mutagenesisi371 – 3711A → Q: Almost total loss of transcriptional activity. 1 Publication
    Mutagenesisi399 – 3991F → W: Slight loss of transcriptional activity. 1 Publication
    Mutagenesisi441 – 4411K → R: No effect on sumoylation. 1 Publication
    Mutagenesisi484 – 4841H → W: Almost total loss of transcriptional activity. 1 Publication
    Mutagenesisi507 – 5071Y → A: Complete loss of transcriptional activity; when associated with A-339. 1 Publication
    Mutagenesisi507 – 5071Y → F: About 40% loss of transcriptional activity. 1 Publication
    Mutagenesisi509 – 5091E → K: Abolishes transcriptional activity. Protects from protein degradation. 2 Publications
    Mutagenesisi510 – 5112LF → AA: Decreases interaction with NCOA2.

    Organism-specific databases

    PharmGKBiPA34630.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 523523Nuclear receptor ROR-alphaPRO_0000053512Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei38 – 381N6-methyllysine1 Publication
    Modified residuei183 – 1831Phosphothreonine; by MAPK12 Publications
    Cross-linki240 – 240Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)

    Post-translational modificationi

    Phosphorylation by conventional PKCs in neurons inhibits transcriptional activity. Phosphorylated on Thr-183 by MAPK1/ERK1 in vitro.2 Publications
    Sumoylated by SENP1 and SENP2. Sumoylation, promoted by PIAS2, PIAS3, PIAS4 but not PIAS1, enhances the transcriptional activity. Desumoylated by SENP1.1 Publication
    Ubiquitinated, leading to its degradation by the proteasome. Proteasomal degradation is required for efficient transcriptional activity and is prevented by HR.1 Publication
    Isoform 1: monomethylated at Lys-38 by EZH2, this creates a degron recognized by a DCX (DDB1-DCAF1/VPRBP-CUL4A-RBX1) E3 ubiquitin ligase complex.1 Publication

    Keywords - PTMi

    Isopeptide bond, Methylation, Phosphoprotein, Ubl conjugation

    Proteomic databases

    PaxDbiP35398.
    PRIDEiP35398.

    PTM databases

    PhosphoSiteiP35398.

    Expressioni

    Tissue specificityi

    Widely expressed in a number of tissues.1 Publication

    Inductioni

    Induced by oxidative stress and DNA damage. Isoform 4 is induced by hypoxia (through transactivation by HIF1A and SP1), but not isoform 1.2 Publications

    Gene expression databases

    ArrayExpressiP35398.
    BgeeiP35398.
    CleanExiHS_RORA.
    GenevestigatoriP35398.

    Organism-specific databases

    HPAiCAB009861.

    Interactioni

    Subunit structurei

    Monomer. Interacts (via the DNA-binding domain) with HIF1A; the interaction enhances HIF1A transcription under hypoxia through increasing protein stability. Interacts with CEBPB; the interaction disrupts the interaction CEBPB:EP300. Interacts with the coactivators NCOA2, PPARGC1A (via LXXLL motif), EP300 and MED1. Interacts with the corepressor NCOR1. Interacts with MAGED1 and CTNNB1. Interacts with CRY1 and PER2.8 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    NR0B1P518432EBI-748689,EBI-946109

    Protein-protein interaction databases

    BioGridi112022. 23 interactions.
    DIPiDIP-29938N.
    IntActiP35398. 5 interactions.
    MINTiMINT-2855668.
    STRINGi9606.ENSP00000261523.

    Structurei

    Secondary structure

    1
    523
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi271 – 28616
    Helixi292 – 2976
    Turni298 – 3003
    Helixi305 – 3139
    Helixi316 – 34025
    Turni342 – 3465
    Helixi349 – 36719
    Helixi368 – 3714
    Turni374 – 3774
    Beta strandi378 – 3814
    Beta strandi384 – 3863
    Helixi388 – 3947
    Helixi397 – 41115
    Helixi417 – 42812
    Helixi439 – 46022
    Helixi466 – 49429
    Helixi496 – 5027
    Helixi505 – 5106

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1N83X-ray1.63A271-523[»]
    1S0XX-ray2.20A271-523[»]
    ProteinModelPortaliP35398.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP35398.

    Family & Domainsi

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni139 – 271133HingeAdd
    BLAST
    Regioni272 – 523252Ligand-bindingAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi506 – 52318AF-2Add
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi166 – 1694Poly-Gln

    Domaini

    The AF-2 (activation function-2) motif is required for recruiting coregulators containing LXXLL motifs.By similarity

    Sequence similaritiesi

    Contains 1 nuclear receptor DNA-binding domain.PROSITE-ProRule annotation

    Zinc finger

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Zinc fingeri73 – 9321NR C4-typePROSITE-ProRule annotationAdd
    BLAST
    Zinc fingeri109 – 13325NR C4-typePROSITE-ProRule annotationAdd
    BLAST

    Keywords - Domaini

    Zinc-finger

    Phylogenomic databases

    eggNOGiNOG324222.
    HOGENOMiHOG000010200.
    HOVERGENiHBG106848.
    InParanoidiP35398.
    KOiK08532.
    OMAiGHCLTGQ.
    OrthoDBiEOG79PJNW.
    TreeFamiTF319910.

    Family and domain databases

    Gene3Di1.10.565.10. 2 hits.
    3.30.50.10. 1 hit.
    InterProiIPR008946. Nucl_hormone_rcpt_ligand-bd.
    IPR000536. Nucl_hrmn_rcpt_lig-bd_core.
    IPR003079. ROR_rcpt.
    IPR001723. Str_hrmn_rcpt.
    IPR001628. Znf_hrmn_rcpt.
    IPR013088. Znf_NHR/GATA.
    [Graphical view]
    PfamiPF00104. Hormone_recep. 1 hit.
    PF00105. zf-C4. 1 hit.
    [Graphical view]
    PRINTSiPR01293. RORNUCRECPTR.
    PR00398. STRDHORMONER.
    PR00047. STROIDFINGER.
    SMARTiSM00430. HOLI. 1 hit.
    SM00399. ZnF_C4. 1 hit.
    [Graphical view]
    SUPFAMiSSF48508. SSF48508. 1 hit.
    PROSITEiPS00031. NUCLEAR_REC_DBD_1. 1 hit.
    PS51030. NUCLEAR_REC_DBD_2. 1 hit.
    [Graphical view]

    Sequences (4)i

    Sequence statusi: Complete.

    This entry describes 4 isoformsi produced by alternative promoter usage and alternative splicing. Align

    Isoform 1 (identifier: P35398-2) [UniParc]FASTAAdd to Basket

    Also known as: Alpha-1

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MESAPAAPDP AASEPGSSGA DAAAGSRETP LNQESARKSE PPAPVRRQSY    50
    SSTSRGISVT KKTHTSQIEI IPCKICGDKS SGIHYGVITC EGCKGFFRRS 100
    QQSNATYSCP RQKNCLIDRT SRNRCQHCRL QKCLAVGMSR DAVKFGRMSK 150
    KQRDSLYAEV QKHRMQQQQR DHQQQPGEAE PLTPTYNISA NGLTELHDDL 200
    SNYIDGHTPE GSKADSAVSS FYLDIQPSPD QSGLDINGIK PEPICDYTPA 250
    SGFFPYCSFT NGETSPTVSM AELEHLAQNI SKSHLETCQY LREELQQITW 300
    QTFLQEEIEN YQNKQREVMW QLCAIKITEA IQYVVEFAKR IDGFMELCQN 350
    DQIVLLKAGS LEVVFIRMCR AFDSQNNTVY FDGKYASPDV FKSLGCEDFI 400
    SFVFEFGKSL CSMHLTEDEI ALFSAFVLMS ADRSWLQEKV KIEKLQQKIQ 450
    LALQHVLQKN HREDGILTKL ICKVSTLRAL CGRHTEKLMA FKAIYPDIVR 500
    LHFPPLYKEL FTSEFEPAMQ IDG 523
    Length:523
    Mass (Da):58,975
    Last modified:April 16, 2014 - v2
    Checksum:i0FA43BBCE6E28DC7
    GO
    Isoform 2 (identifier: P35398-1) [UniParc]FASTAAdd to Basket

    Also known as: Alpha-2

    The sequence of this isoform differs from the canonical sequence as follows:
         1-66: MESAPAAPDP...ISVTKKTHTS → MNEGAPGDSD...KEVQTGYMNA

    Note: Produced by alternative promoter usage. Region from 23 to 71 inhibits DNA-binding and transactivation activity.

    Show »
    Length:556
    Mass (Da):63,036
    Checksum:i0D9797A147CEE8AE
    GO
    Isoform 3 (identifier: P35398-3) [UniParc]FASTAAdd to Basket

    Also known as: Alpha-3

    The sequence of this isoform differs from the canonical sequence as follows:
         38-65: KSEPPAPVRRQSYSSTSRGISVTKKTHT → SSSTCSSLSRLFWSQLEHINWDGATAKNFINLREFFSFLLPALRK

    Note: Produced by alternative splicing.

    Show »
    Length:540
    Mass (Da):61,108
    Checksum:i89FEA2A06D25D971
    GO
    Isoform 4 (identifier: P35398-4) [UniParc]FASTAAdd to Basket

    Also known as: Alpha-4

    The sequence of this isoform differs from the canonical sequence as follows:
         1-65: MESAPAAPDPAASEPGSSGADAAAGSRETPLNQESARKSEPPAPVRRQSYSSTSRGISVTKKTHT → MMYFVIAAMK

    Note: Produced by alternative promoter usage.Curated

    Show »
    Length:468
    Mass (Da):53,556
    Checksum:iFD577090E6261B16
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti368 – 3681M → V in AAA02963. (PubMed:7916608)Curated
    Sequence conflicti466 – 4661I → M in AAA02963. (PubMed:7916608)Curated
    Isoform 4 (identifier: P35398-4)
    Sequence conflicti7 – 71A → E in AAA02963. (PubMed:7916608)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Isoform 2 (identifier: P35398-1)
    Natural varianti18 – 181P → S in a colorectal cancer sample, somatic mutation.

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 6666MESAP…KTHTS → MNEGAPGDSDLETEARVPWS IMGHCLRTGQARMSATPTPA GEGARRDELFGILQILHQCI LSSGDAFVLTGVCCSWRQNG KPPYSQKEDKEVQTGYMNA in isoform 2. 1 PublicationVSP_053973Add
    BLAST
    Alternative sequencei1 – 6565MESAP…KKTHT → MMYFVIAAMK in isoform 4. 3 PublicationsVSP_053974Add
    BLAST
    Alternative sequencei38 – 6528KSEPP…KKTHT → SSSTCSSLSRLFWSQLEHIN WDGATAKNFINLREFFSFLL PALRK in isoform 3. 1 PublicationVSP_053975Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U04897 mRNA. Translation: AAA62658.1.
    U04898 mRNA. Translation: AAA62659.1.
    U04899 mRNA. Translation: AAA62660.1.
    L14611 mRNA. Translation: AAA02963.1.
    HQ692818 mRNA. Translation: ADZ17329.1.
    AC009560 Genomic DNA. No translation available.
    AC012404 Genomic DNA. No translation available.
    AC022898 Genomic DNA. No translation available.
    AC079068 Genomic DNA. No translation available.
    AC087385 Genomic DNA. No translation available.
    AC107241 Genomic DNA. No translation available.
    AC107905 Genomic DNA. No translation available.
    CH471082 Genomic DNA. Translation: EAW77594.1.
    BC008831 mRNA. Translation: AAH08831.1.
    BC100987 mRNA. Translation: AAI00988.1.
    BC100988 mRNA. Translation: AAI00989.1.
    BC100989 mRNA. Translation: AAI00990.1.
    BC100990 mRNA. Translation: AAI00991.1.
    CCDSiCCDS10177.1. [P35398-2]
    CCDS10179.1. [P35398-1]
    CCDS45271.1. [P35398-4]
    PIRiA53196.
    A56856.
    B53196.
    C53196.
    RefSeqiNP_002934.1. NM_002943.3.
    NP_599022.1. NM_134260.2. [P35398-1]
    NP_599023.1. NM_134261.2. [P35398-2]
    NP_599024.1. NM_134262.2.
    UniGeneiHs.560343.
    Hs.655155.

    Genome annotation databases

    EnsembliENST00000261523; ENSP00000261523; ENSG00000069667. [P35398-1]
    ENST00000309157; ENSP00000309753; ENSG00000069667. [P35398-3]
    ENST00000335670; ENSP00000335087; ENSG00000069667. [P35398-2]
    ENST00000449337; ENSP00000402971; ENSG00000069667. [P35398-4]
    GeneIDi6095.
    KEGGihsa:6095.
    UCSCiuc002agt.4. human. [P35398-4]
    uc002agv.3. human. [P35398-2]
    uc002agw.3. human. [P35398-3]
    uc002agx.3. human. [P35398-2]

    Polymorphism databases

    DMDMi548814.

    Keywords - Coding sequence diversityi

    Alternative promoter usage, Alternative splicing, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U04897 mRNA. Translation: AAA62658.1 .
    U04898 mRNA. Translation: AAA62659.1 .
    U04899 mRNA. Translation: AAA62660.1 .
    L14611 mRNA. Translation: AAA02963.1 .
    HQ692818 mRNA. Translation: ADZ17329.1 .
    AC009560 Genomic DNA. No translation available.
    AC012404 Genomic DNA. No translation available.
    AC022898 Genomic DNA. No translation available.
    AC079068 Genomic DNA. No translation available.
    AC087385 Genomic DNA. No translation available.
    AC107241 Genomic DNA. No translation available.
    AC107905 Genomic DNA. No translation available.
    CH471082 Genomic DNA. Translation: EAW77594.1 .
    BC008831 mRNA. Translation: AAH08831.1 .
    BC100987 mRNA. Translation: AAI00988.1 .
    BC100988 mRNA. Translation: AAI00989.1 .
    BC100989 mRNA. Translation: AAI00990.1 .
    BC100990 mRNA. Translation: AAI00991.1 .
    CCDSi CCDS10177.1. [P35398-2 ]
    CCDS10179.1. [P35398-1 ]
    CCDS45271.1. [P35398-4 ]
    PIRi A53196.
    A56856.
    B53196.
    C53196.
    RefSeqi NP_002934.1. NM_002943.3.
    NP_599022.1. NM_134260.2. [P35398-1 ]
    NP_599023.1. NM_134261.2. [P35398-2 ]
    NP_599024.1. NM_134262.2.
    UniGenei Hs.560343.
    Hs.655155.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1N83 X-ray 1.63 A 271-523 [» ]
    1S0X X-ray 2.20 A 271-523 [» ]
    ProteinModelPortali P35398.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 112022. 23 interactions.
    DIPi DIP-29938N.
    IntActi P35398. 5 interactions.
    MINTi MINT-2855668.
    STRINGi 9606.ENSP00000261523.

    Chemistry

    BindingDBi P35398.
    ChEMBLi CHEMBL5868.
    GuidetoPHARMACOLOGYi 598.

    PTM databases

    PhosphoSitei P35398.

    Polymorphism databases

    DMDMi 548814.

    Proteomic databases

    PaxDbi P35398.
    PRIDEi P35398.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000261523 ; ENSP00000261523 ; ENSG00000069667 . [P35398-1 ]
    ENST00000309157 ; ENSP00000309753 ; ENSG00000069667 . [P35398-3 ]
    ENST00000335670 ; ENSP00000335087 ; ENSG00000069667 . [P35398-2 ]
    ENST00000449337 ; ENSP00000402971 ; ENSG00000069667 . [P35398-4 ]
    GeneIDi 6095.
    KEGGi hsa:6095.
    UCSCi uc002agt.4. human. [P35398-4 ]
    uc002agv.3. human. [P35398-2 ]
    uc002agw.3. human. [P35398-3 ]
    uc002agx.3. human. [P35398-2 ]

    Organism-specific databases

    CTDi 6095.
    GeneCardsi GC15M060780.
    HGNCi HGNC:10258. RORA.
    HPAi CAB009861.
    MIMi 600825. gene.
    neXtProti NX_P35398.
    PharmGKBi PA34630.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG324222.
    HOGENOMi HOG000010200.
    HOVERGENi HBG106848.
    InParanoidi P35398.
    KOi K08532.
    OMAi GHCLTGQ.
    OrthoDBi EOG79PJNW.
    TreeFami TF319910.

    Enzyme and pathway databases

    Reactomei REACT_111118. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
    REACT_116145. PPARA activates gene expression.
    REACT_118659. RORA activates circadian gene expression.
    REACT_118789. REV-ERBA represses gene expression.
    REACT_15525. Nuclear Receptor transcription pathway.
    REACT_24941. Circadian Clock.
    SignaLinki P35398.

    Miscellaneous databases

    ChiTaRSi RORA. human.
    EvolutionaryTracei P35398.
    GeneWikii RAR-related_orphan_receptor_alpha.
    GenomeRNAii 6095.
    NextBioi 23703.
    PROi P35398.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P35398.
    Bgeei P35398.
    CleanExi HS_RORA.
    Genevestigatori P35398.

    Family and domain databases

    Gene3Di 1.10.565.10. 2 hits.
    3.30.50.10. 1 hit.
    InterProi IPR008946. Nucl_hormone_rcpt_ligand-bd.
    IPR000536. Nucl_hrmn_rcpt_lig-bd_core.
    IPR003079. ROR_rcpt.
    IPR001723. Str_hrmn_rcpt.
    IPR001628. Znf_hrmn_rcpt.
    IPR013088. Znf_NHR/GATA.
    [Graphical view ]
    Pfami PF00104. Hormone_recep. 1 hit.
    PF00105. zf-C4. 1 hit.
    [Graphical view ]
    PRINTSi PR01293. RORNUCRECPTR.
    PR00398. STRDHORMONER.
    PR00047. STROIDFINGER.
    SMARTi SM00430. HOLI. 1 hit.
    SM00399. ZnF_C4. 1 hit.
    [Graphical view ]
    SUPFAMi SSF48508. SSF48508. 1 hit.
    PROSITEi PS00031. NUCLEAR_REC_DBD_1. 1 hit.
    PS51030. NUCLEAR_REC_DBD_2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors."
      Giguere V., Tini M., Flock G., Ong E., Evans R.M., Otulakowski G.
      Genes Dev. 8:538-553(1994) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3), FUNCTION AS TRANSCRIPTION ACTIVATOR, DNA-BINDING, SUBUNIT.
      Tissue: Retina and Testis.
    2. "Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences."
      Becker-Andre M., Andre E., Delamarter J.F.
      Biochem. Biophys. Res. Commun. 194:1371-1379(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), TISSUE SPECIFICITY.
      Tissue: Umbilical vein endothelial cell.
    3. "Isolation of cDNA coding for multiple human nuclear receptor clones."
      Kaighin V.A., Martin A.L., Aronstam R.S.
      Submitted (DEC-2010) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
      Tissue: Kidney.
    4. "Analysis of the DNA sequence and duplication history of human chromosome 15."
      Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., Abouelleil A.
      , Arachchi H.M., Baradarani L., Birditt B., Bloom S., Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.
      Nature 440:671-675(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4).
      Tissue: Muscle.
    7. "Transcriptional activation and repression by RORalpha, an orphan nuclear receptor required for cerebellar development."
      Harding H.P., Atkins G.B., Jaffe A.B., Seo W.J., Lazar M.A.
      Mol. Endocrinol. 11:1737-1746(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION AS TRANSCRIPTION ACTIVATOR, INTERACTION WITH NCOR1, DNA-BINDING, SUBUNIT.
    8. Cited for: FUNCTION AS TRANSCRIPTION ACTIVATOR, INTERACTION WITH MED1 AND NCOA2, MUTAGENESIS OF VAL-335 AND 510-LEU-PHE-511.
    9. "Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: RORalpha1 directly interacts with p300 and myoD."
      Lau P., Bailey P., Dowhan D.H., Muscat G.E.
      Nucleic Acids Res. 27:411-420(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN MYOGENESIS, INTERACTION WITH EP300.
    10. "Identification of a novel peroxisome proliferator-activated receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor RORalpha1."
      Sundvold H., Lien S.
      Biochem. Biophys. Res. Commun. 287:383-390(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION AS TRANSCRIPTION ACTIVATOR, DNA-BINDING.
    11. "The orphan nuclear receptor ROR alpha is a negative regulator of the inflammatory response."
      Delerive P., Monte D., Dubois G., Trottein F., Fruchart-Najib J., Mariani J., Fruchart J.C., Staels B.
      EMBO Rep. 2:42-48(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN INFLAMMATION.
    12. "Transcriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor RORalpha."
      Raspe E., Duez H., Gervois P., Fievet C., Fruchart J.C., Besnard S., Mariani J., Tedgui A., Staels B.
      J. Biol. Chem. 276:2865-2871(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN TRIGLYCERIDE METABOLISM, DNA-BINDING.
    13. "The co-repressor hairless protects RORalpha orphan nuclear receptor from proteasome-mediated degradation."
      Moraitis A.N., Giguere V.
      J. Biol. Chem. 278:52511-52518(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION AS TRANSCRIPTION ACTIVATOR, UBIQUITINATION, MUTAGENESIS OF LYS-357; LEU-361; VAL-364 AND GLU-509.
    14. "Hypoxia-induced activation of the retinoic acid receptor-related orphan receptor alpha4 gene by an interaction between hypoxia-inducible factor-1 and Sp1."
      Miki N., Ikuta M., Matsui T.
      J. Biol. Chem. 279:15025-15031(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: INDUCTION BY HYPOXIA (ISOFORM 4).
    15. Cited for: FUNCTION IN TRIGLYCERIDE METABOLISM, DNA-BINDING.
    16. Cited for: FUNCTION IN TRIGLYCERIDE METABOLISM, DNA-BINDING.
    17. "RORA, a large common fragile site gene, is involved in cellular stress response."
      Zhu Y., McAvoy S., Kuhn R., Smith D.I.
      Oncogene 25:2901-2908(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN CELL GROWTH, INDUCTION BY CELLULAR STRESS.
    18. Cited for: PHOSPHORYLATION AT THR-183, FUNCTION, MUTAGENESIS OF THR-183.
    19. "Transcriptional activation of HIF-1 by RORalpha and its role in hypoxia signaling."
      Kim E.J., Yoo Y.G., Yang W.K., Lim Y.S., Na T.Y., Lee I.K., Lee M.O.
      Arterioscler. Thromb. Vasc. Biol. 28:1796-1802(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN HYPOXIA SIGNALING, INTERACTION WITH HIF1A, INDUCTION BY HYPOXIA, SUBCELLULAR LOCATION.
    20. "Phosphorylation and transcriptional activity regulation of retinoid-related orphan receptor alpha 1 by protein kinases C."
      Duplus E., Gras C., Soubeyre V., Vodjdani G., Lemaigre-Dubreuil Y., Brugg B.
      J. Neurochem. 104:1321-1332(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION AS TRANSCRIPTION ACTIVATOR, PHOSPHORYLATION, SUBCELLULAR LOCATION.
    21. "SUMOylation of RORalpha potentiates transcriptional activation function."
      Hwang E.J., Lee J.M., Jeong J., Park J.H., Yang Y., Lim J.S., Kim J.H., Baek S.H., Kim K.I.
      Biochem. Biophys. Res. Commun. 378:513-517(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUMOYLATION AT LYS-240, MUTAGENESIS OF LYS-240 AND LYS-441.
    22. "Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism."
      Jetten A.M.
      Nucl. Recept. Signal. 7:3-35(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON FUNCTION.
    23. "Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands."
      Wang Y., Kumar N., Solt L.A., Richardson T.I., Helvering L.M., Crumbley C., Garcia-Ordonez R.D., Stayrook K.R., Zhang X., Novick S., Chalmers M.J., Griffin P.R., Burris T.P.
      J. Biol. Chem. 285:5013-5025(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN GLUCOSE METABOLISM REGULATION, IDENTIFICATION OF LIGANDS.
    24. Cited for: FUNCTION IN T(H)17 CELLS DIFFERENTIATION, IDENTIFICATION OF LIGANDS.
    25. "Cryptochromes mediate rhythmic repression of the glucocorticoid receptor."
      Lamia K.A., Papp S.J., Yu R.T., Barish G.D., Uhlenhaut N.H., Jonker J.W., Downes M., Evans R.M.
      Nature 480:552-556(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH CRY1.
    26. "EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex."
      Lee J.M., Lee J.S., Kim H., Kim K., Park H., Kim J.Y., Lee S.H., Kim I.S., Kim J., Lee M., Chung C.H., Seo S.B., Yoon J.B., Ko E., Noh D.Y., Kim K.I., Kim K.K., Baek S.H.
      Mol. Cell 48:572-586(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: METHYLATION AT LYS-38.
    27. "Action of RORs and their ligands in (patho)physiology."
      Solt L.A., Burris T.P.
      Trends Endocrinol. Metab. 23:619-627(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON FUNCTION AND LIGANDS.
    28. Cited for: VARIANT [LARGE SCALE ANALYSIS] SER-18 (ISOFORM 2).
    29. "X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha."
      Kallen J.A., Schlaeppi J.-M., Bitsch F., Geisse S., Geiser M., Delhon I., Fournier B.
      Structure 10:1697-1707(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.63 ANGSTROMS) OF 271-523 IN COMPLEX WITH CHOLESTEROL, FUNCTION AS TRANSCRIPTION ACTIVATOR, IDENTIFICATION OF LIGANDS, MUTAGENESIS OF CYS-323; ALA-330; ALA-371; PHE-399; HIS-484 AND TYR-507, IDENTIFICATION BY MASS SPECTROMETRY.
    30. "Crystal structure of the human RORalpha Ligand binding domain in complex with cholesterol sulfate at 2.2 A."
      Kallen J., Schlaeppi J.-M., Bitsch F., Delhon I., Fournier B.
      J. Biol. Chem. 279:14033-14038(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 271-523 IN COMPLEX WITH CHOLESTEROL SULFATE, MUTAGENESIS OF CYS-288; CYS-323; ALA-330; LYS-339 AND GLU-509, IDENTIFICATION BY MASS SPECTROMETRY.

    Entry informationi

    Entry nameiRORA_HUMAN
    AccessioniPrimary (citable) accession number: P35398
    Secondary accession number(s): P35397
    , P35399, P45445, Q495X4, Q96H83
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: June 1, 1994
    Last sequence update: April 16, 2014
    Last modified: October 1, 2014
    This is version 152 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 15
      Human chromosome 15: entries, gene names and cross-references to MIM
    2. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    4. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3