P11474 (ERR1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Steroid hormone receptor ERR1

Alternative name(s):
Estrogen receptor-like 1
Estrogen-related receptor alpha
Short name=ERR-alpha
Nuclear receptor subfamily 3 group B member 1

Gene names

Name:	ESRRA
Synonyms:	ERR1, ESRL1, NR3B1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	423 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5'-TNAAGGTCA-3'. Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alpha complex is a regulator of energy metabolism. Ref.5 Ref.6 Ref.7 Ref.8 Ref.9
Subunit structure	Binds DNA as a monomer or a homodimer. Interacts (via the AF2 domain) with coactivator PPARGC1A (via the L3 motif); the interaction greatly enhances transriptional activity of genes involved in energy metabolism. Interacts with PIAS4; the interaction enhances sumoylation. Ref.6 Ref.7 Ref.9 Ref.11 Ref.12
Subcellular location	Nucleus Ref.9.
Induction	Induced by PGC1alpha in a number of specific cell types including heart, kidney and muscle. Ref.6
Post-translational modification	Phosphorylation on Ser-19 enhances sumoylation on Lys-14 increasing repression of transcriptional activity. Ref.8 Ref.9 Sumoylated with SUMO2. Main site is Lys-14 which is enhanced by phosphorylation on Ser-19, cofactor activation, and by interaction with PIAS4. Sumoylation enhances repression of transcriptional activiy, but has no effect on subcellular location nor on DNA binding. Ref.8 Ref.9
Sequence similarities	Belongs to the nuclear hormone receptor family. NR3 subfamily. Contains 1 nuclear receptor DNA-binding domain.
Sequence caution	The sequence AAB17015.1 differs from that shown. Reason: Erroneous initiation. The sequence CAA35778.1 differs from that shown. Reason: Frameshift at positions 345 and 354.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing
Domain	Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Receptor
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	cartilage development Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from sequence or structural similarity. Source: BHF-UCL regulation of cell proliferation Inferred from electronic annotation. Source: Compara regulation of osteoblast differentiation Inferred from electronic annotation. Source: Compara regulation of osteoclast differentiation Inferred from electronic annotation. Source: Compara transcription initiation from RNA polymerase II promoter Traceable author statement. Source: Reactome
Cellular_component	nucleoplasm Traceable author statement. Source: Reactome
Molecular_function	DNA binding Traceable author statement PubMed 9286700. Source: ProtInc ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity Traceable author statement PubMed 9286700. Source: ProtInc sequence-specific DNA binding Inferred from electronic annotation. Source: InterPro steroid binding Inferred from electronic annotation. Source: InterPro steroid hormone receptor activity Inferred from electronic annotation. Source: InterPro zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
TRRAP	Q9Y4A5	3	EBI-372412,EBI-399128

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P11474-1)

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.

Isoform 2 (identifier: P11474-2)

The sequence of this isoform differs from the canonical sequence as follows:
     191-191: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 423

423

Steroid hormone receptor ERR1

PRO_0000053660

Regions

DNA binding

76 – 151

76

Nuclear receptor Ref.7

Zinc finger

79 – 99

21

NR C4-type

Zinc finger

115 – 134

20

NR C4-type

Region

1 – 76

76

Repressor domain

Region

206 – 402

197

Ligand binding domain

Region

403 – 423

21

AF-2 domain

Sites

Site

124

1

Required for DNA-dependent dimerization

Amino acid modifications

Modified residue

19

1

Phosphoserine Ref.8 Ref.9 Ref.10

Modified residue

22

1

Phosphoserine Ref.8 Ref.9 Ref.10

Cross-link

14

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.8 Ref.9

Cross-link

403

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO); partial Ref.8 Ref.9

Natural variations

Alternative sequence

191

1

Missing in isoform 2.

VSP_035756

Experimental info

Mutagenesis

14

1

K → R: Some loss of sumoylation. Complete loss of sumoylation; when associated with R-403. Ref.8 Ref.9

Mutagenesis

19

1

S → A: 50% loss of phosphorylation but represses transactivation activity in the absence of coactivator. Almost complete loss of phosphorylation and 2-fold loss of repression of transactivation activity in response to coactivator; when associated with A-22. Ref.8 Ref.9

Mutagenesis

19

1

S → D: Represses transactivation activity in response to coactivator as for wild type; when associated with D-22. Ref.8 Ref.9

Mutagenesis

22

1

S → A: 15% loss of phosphorylation but little transactivating activity. Almost complete loss of phosphorylation and 2-fold loss of repression of transactivation activity in the presence of coactivator; when associated with A-19. Ref.8 Ref.9

Mutagenesis

22

1

S → D: Represses transactivation activity in response to coactivator as for wild type; when associated with D-19. Ref.8 Ref.9

Mutagenesis

118

1

S → A: Binds DNA as a monomer or as a dimer as for wild type. No effect on interaction with PPARGC1A. Ref.7

Mutagenesis

124

1

T → A: Binds DNA predominantly as a monomer. Loss of interaction with PPARGC1A. Ref.7

Mutagenesis

258 – 262

5

MSVLQ → VSVLE: Almost complete loss of interaction to L2 or to L3 of PPARGC1A. Ref.12

Mutagenesis

259

1

S → H: Little effect on binding L2 of PPARGC1A. Greatly reduced binding to L3 of PPARGC1A. Ref.12

Mutagenesis

315

1

R → A: Almost complete loss of interaction to L2 or to L3 of PPARGC1A. Ref.12

Mutagenesis

338

1

D → A: Almost complete loss of interaction to L2 or to L3 of PPARGC1A. Ref.12

Mutagenesis

341

1

H → A: Little effect on binding L3 of PPARGC1A. Ref.12

Mutagenesis

343

1

E → A: No effect on binding L3 of PPARGC1A. Ref.12

Mutagenesis

403

1

K → R: Decrease in sumoylation. No effect on transcriptional activity. Complete loss of sumoylation; when associated with R-14. Ref.8 Ref.9

Mutagenesis

413

1

L → A: Loss of coactivation activity; when associated with A-418. Loss of increased response to coactivator; when associated with A-19 and A-418. Ref.8

Mutagenesis

418

1

L → A: Loss of coactivation activity; when associated with A-413. Loss of increased response to coactivator activity; when associated with A-19 and A-413. Ref.8

Mutagenesis

421 – 423

3

Missing: Greatly reduced interaction with L3 motif of PPARGC1A. Less effect on binding to L2 motif of PPARGC1A. Ref.12

Mutagenesis

423

1

D → A: Little effect on binding L3 of PPARGC1A.

Secondary structure

1

.

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423

Helix Strand Turn

Details...

Helix

195 – 204

10

Helix

224 – 244

21

Helix

249 – 251

3

Helix

254 – 277

24

Beta strand

280 – 282

3

Beta strand

284 – 287

4

Beta strand

290 – 292

3

Helix

294 – 299

6

Turn

300 – 304

5

Helix

305 – 317

13

Turn

318 – 320

3

Helix

323 – 335

13

Helix

345 – 364

20

Helix

377 – 382

6

Helix

385 – 400

16

Helix

404 – 406

3

Helix

410 – 421

12

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 25, 2008. Version 3. Checksum: BAE62DAF0BE6BA96	FASTA	423	45,510
	10 20 30 40 50 60 MSSQVVGIEP LYIKAEPASP DSPKGSSETE TEPPVALAPG PAPTRCLPGH KEEEDGEGAG 70 80 90 100 110 120 PGEQGGGKLV LSSLPKRLCL VCGDVASGYH YGVASCEACK AFFKRTIQGS IEYSCPASNE 130 140 150 160 170 180 CEITKRRRKA CQACRFTKCL RVGMLKEGVR LDRVRGGRQK YKRRPEVDPL PFPGPFPAGP 190 200 210 220 230 240 LAVAGGPRKT AAPVNALVSH LLVVEPEKLY AMPDPAGPDG HLPAVATLCD LFDREIVVTI 250 260 270 280 290 300 SWAKSIPGFS SLSLSDQMSV LQSVWMEVLV LGVAQRSLPL QDELAFAEDL VLDEEGARAA 310 320 330 340 350 360 GLGELGAALL QLVRRLQALR LEREEYVLLK ALALANSDSV HIEDAEAVEQ LREALHEALL 370 380 390 400 410 420 EYEAGRAGPG GGAERRRAGR LLLTLPLLRQ TAGKVLAHFY GVKLEGKVPM HKLFLEMLEA MMD
	Isoform 2 [UniParc]. Checksum: 482E152354383842	FASTA	422	45,439
	10 20 30 40 50 60 MSSQVVGIEP LYIKAEPASP DSPKGSSETE TEPPVALAPG PAPTRCLPGH KEEEDGEGAG 70 80 90 100 110 120 PGEQGGGKLV LSSLPKRLCL VCGDVASGYH YGVASCEACK AFFKRTIQGS IEYSCPASNE 130 140 150 160 170 180 CEITKRRRKA CQACRFTKCL RVGMLKEGVR LDRVRGGRQK YKRRPEVDPL PFPGPFPAGP 190 200 210 220 230 240 LAVAGGPRKT APVNALVSHL LVVEPEKLYA MPDPAGPDGH LPAVATLCDL FDREIVVTIS 250 260 270 280 290 300 WAKSIPGFSS LSLSDQMSVL QSVWMEVLVL GVAQRSLPLQ DELAFAEDLV LDEEGARAAG 310 320 330 340 350 360 LGELGAALLQ LVRRLQALRL EREEYVLLKA LALANSDSVH IEDAEAVEQL REALHEALLE 370 380 390 400 410 420 YEAGRAGPGG GAERRRAGRL LLTLPLLRQT AGKVLAHFYG VKLEGKVPMH KLFLEMLEAM MD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of a new class of steroid hormone receptors." Giguere V., Yang N., Segui P., Evans R.M. Nature 331:91-94(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Kidney.
[2]	"Estrogen-related receptor, hERR1, modulates estrogen receptor-mediated response of human lactoferrin gene promoter." Yang N., Shigeta H., Shi H., Teng C.T. J. Biol. Chem. 271:5795-5804(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Uterus.
[3]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"SV40 early-to-late switch involves titration of cellular transcriptional repressors." Wiley S.R., Kraus R.J., Zuo F., Murray E.E., Loritz K., Mertz J.E. Genes Dev. 7:2206-2219(1993) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 69-76.
[5]	"The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene." Sladek R., Bader J.-A., Giguere V. Mol. Cell. Biol. 17:5400-5409(1997) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[6]	"The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha)." Schreiber S.N., Knutti D., Brogli K., Uhlmann T., Kralli A. J. Biol. Chem. 278:9013-9018(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PPARGC1A, INDUCTION, FUNCTION.
[7]	"A single nucleotide in an estrogen-related receptor alpha site can dictate mode of binding and peroxisome proliferator-activated receptor gamma coactivator 1alpha activation of target promoters." Barry J.B., Laganiere J., Giguere V. Mol. Endocrinol. 20:302-310(2006) [PubMed] [Europe PMC] [Abstract] Cited for: DNA-BINDING SPECIFICITY, INTERACTION WITH PPARGC1A, HOMODIMERIZATION, FUNCTION, MUTAGENESIS OF SER-118 AND THR-124.
[8]	"Phosphorylation-dependent sumoylation of estrogen-related receptor alpha1." Vu E.H., Kraus R.J., Mertz J.E. Biochemistry 46:9795-9804(2007) [PubMed] [Europe PMC] [Abstract] Cited for: SUMOYLATION AT LYS-14 AND LYS-403, PHOSPHORYLATION AT SER-19 AND SER-22, FUNCTION, MUTAGENESIS OF LYS-14; SER-19; SER-22; LYS-403; LEU-413 AND LEU-418.
[9]	"Phosphorylation-dependent sumoylation regulates estrogen-related receptor-alpha and -gamma transcriptional activity through a synergy control motif." Tremblay A.M., Wilson B.J., Yang X.-J., Giguere V. Mol. Endocrinol. 22:570-584(2008) [PubMed] [Europe PMC] [Abstract] Cited for: SUMOYLATION AT LYS-14 AND LYS-403, PHOSPHORYLATION AT SER-19 AND SER-22, INTERACTION WITH PIAS4, FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-14; SER-19; SER-22 AND LYS-403.
[10]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-19 AND SER-22, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[11]	"Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor alpha (ERRalpha): crystal structure of ERRalpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1alpha." Kallen J., Schlaeppi J.-M., Bitsch F., Filipuzzi I., Schilb A., Riou V., Graham A., Strauss A., Geiser M., Fournier B. J. Biol. Chem. 279:49330-49337(2004) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 193-423 IN COMPLEX WITH THE L3 SITE-CONTAINING PEPTIDE OF COACTIVATOR PPARGC1A, HOMODIMERIZATION, MASS SPECTROMETRY.
[12]	"Communication between the ERRalpha homodimer interface and the PGC-1alpha binding surface via the helix 8-9 loop." Greschik H., Althage M., Flaig R., Sato Y., Chavant V., Peluso-Iltis C., Choulier L., Cronet P., Rochel N., Schuele R., Stroemstedt P.E., Moras D. J. Biol. Chem. 283:20220-20230(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.11 ANGSTROMS) OF 180-423 IN COMPLEX WITH THE L3 SITE-CONTAINING PEPTIDE OF COACTIVATOR PPARGC1A, INTERACTION WITH PPARGC1A, MUTAGENESIS OF 258-MET--GLN-262; SER-259; ARG-315; ASP-338; HIS-341; GLU-343 AND 421-MET--ASP-423.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X51416 mRNA. Translation: CAA35778.1. Frameshift.
L38487 mRNA. Translation: AAB17015.1. Different initiation.
AP001453 Genomic DNA. No translation available.

IPI

IPI00005717.
IPI00792208.

PIR

A29345.

RefSeq

NP_004442.3. NM_004451.3.

UniGene

Hs.110849.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1XB7	X-ray	2.50	A	193-423	[»]
2PJL	X-ray	2.30	A/B	193-423	[»]
3D24	X-ray	2.11	A/C	189-423	[»]
3K6P	X-ray	2.00	A	193-423	[»]

ProteinModelPortal

P11474.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-35053N.

IntAct

P11474. 11 interactions.

MINT

MINT-215609.

STRING

9606.ENSP00000000442.

PTM databases

PhosphoSite

P11474.

Polymorphism databases

DMDM

215274146.

Proteomic databases

PaxDb

P11474.

PRIDE

P11474.

Protocols and materials databases

DNASU

2101.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000000442; ENSP00000000442; ENSG00000173153.
ENST00000405666; ENSP00000384851; ENSG00000173153.
ENST00000406310; ENSP00000385971; ENSG00000173153.

GeneID

2101.

KEGG

hsa:2101.

UCSC

uc001nzq.1. human.
uc001nzr.1. human.

Organism-specific databases

CTD

2101.

GeneCards

GC11P064073.

HGNC

HGNC:3471. ESRRA.

MIM

601998. gene.

neXtProt

NX_P11474.

PharmGKB

PA27887.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG282629.

HOGENOM

HOG000233467.

HOVERGEN

HBG108344.

KO

K08552.

OMA

PLPFPGS.

OrthoDB

EOG48KRBN.

Enzyme and pathway databases

Reactome

REACT_71. Gene Expression.

Gene expression databases

ArrayExpress

P11474.

Bgee

P11474.

CleanEx

HS_ESRRA.

Genevestigator

P11474.

GermOnline

ENSG00000173153. Homo sapiens.

Family and domain databases

Gene3D

1.10.565.10. 1 hit.
3.30.50.10. 1 hit.

InterPro

IPR008946. Nucl_hormone_rcpt_ligand-bd.
IPR000536. Nucl_hrmn_rcpt_lig-bd_core.
IPR027289. Oest-rel_rcp.
IPR024178. Oest_rcpt/oest-rel_rcp.
IPR001723. Str_hrmn_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]

Pfam

PF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]

PIRSF

PIRSF002527. ER-like_NR. 1 hit.
PIRSF500939. ERR1-2-3. 1 hit.

PRINTS

PR00398. STRDHORMONER.
PR00047. STROIDFINGER.

SMART

SM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view]

SUPFAM

SSF48508. Str_ncl_receptor. 1 hit.

PROSITE

PS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P11474.

ChEMBL

CHEMBL3429.

EvolutionaryTrace

P11474.

GenomeRNAi

2101.

NextBio

8503.

SOURCE

Search...

Entry information

Entry name

ERR1_HUMAN

Accession

Primary (citable) accession number: P11474
Secondary accession number(s): Q14514

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1989
Last sequence update:	November 25, 2008
Last modified:	May 1, 2013
This is version 153 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.