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O00167 (EYA2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 135. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Eyes absent homolog 2

EC=3.1.3.48
Gene names
Name:EYA2
Synonyms:EAB1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length538 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Functions both as protein phosphatase and as transcriptional coactivator for SIX1, and probably also for SIX2, SIX4 and SIX5. Tyrosine phosphatase that dephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph) and promotes efficient DNA repair via the recruitment of DNA repair complexes containing MDC1. 'Tyr-142' phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress. Its function as histone phosphatase may contribute to its function in transcription regulation during organogenesis. Plays an important role in hypaxial muscle development together with SIX1 and DACH2; in this it is functionally redundant with EYA1. Ref.12 Ref.13

Catalytic activity

Protein tyrosine phosphate + H2O = protein tyrosine + phosphate. Ref.13

Cofactor

Binds 1 Mg2+ ion per subunit. Ref.14

Subunit structure

Interacts with DACH2 and SIX1, and probably with SIX2, SIX4 and SIX5. Interacts with CAPN8 By similarity. Interacts with GNAZ and GNAI2; this precludes interaction with SIX1. Ref.9 Ref.11 Ref.15

Subcellular location

Cytoplasm. Nucleus. Note: Retained in the cytoplasm via interaction with GNAZ and GNAI2. Interaction with SIX1, SIX2, SIX4 or SIX5 is required for translocation to the nucleus. Ref.9 Ref.10 Ref.11

Tissue specificity

Highest expression in muscle with lower levels in kidney, placenta, pancreas, brain and heart.

Developmental stage

At the begin of fourth week of development detected in cytoplasm of somite cells. Between the sixth and eighth week of development detected in cytoplasm of limb bud cells. Ref.10

Sequence similarities

Belongs to the HAD-like hydrolase superfamily. EYA family.

Biophysicochemical properties

Kinetic parameters:

KM=1.9 µM for H2AXY142ph Ref.13

KM=80 µM for H2AXS139ph

Sequence caution

The sequence AAH13882.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
   Biological processDNA damage
DNA repair
Transcription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   LigandMagnesium
Metal-binding
   Molecular functionActivator
Chromatin regulator
Developmental protein
Hydrolase
Protein phosphatase
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processDNA repair

Inferred from electronic annotation. Source: UniProtKB-KW

extrinsic apoptotic signaling pathway in absence of ligand

Inferred from electronic annotation. Source: Ensembl

histone dephosphorylation

Inferred from direct assay Ref.13. Source: UniProtKB

mesodermal cell fate specification

Traceable author statement Ref.3. Source: ProtInc

mitochondrial outer membrane permeabilization

Inferred from electronic annotation. Source: Ensembl

peptidyl-tyrosine dephosphorylation

Inferred from direct assay Ref.13. Source: GOC

regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

striated muscle tissue development

Inferred from electronic annotation. Source: Ensembl

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcentrosome

Inferred from direct assay. Source: HPA

cytoplasm

Inferred from direct assay. Source: HPA

mitochondrion

Inferred from electronic annotation. Source: GOC

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionmagnesium ion binding

Inferred from direct assay Ref.13. Source: UniProtKB

protein tyrosine phosphatase activity

Inferred from direct assay Ref.13. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Note: Experimental confirmation may be lacking for some isoforms.
Isoform 1 (identifier: O00167-1)

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: O00167-2)

The sequence of this isoform differs from the canonical sequence as follows:
     99-122: Missing.
Isoform 3 (identifier: O00167-3)

The sequence of this isoform differs from the canonical sequence as follows:
     401-479: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 538538Eyes absent homolog 2
PRO_0000218646

Sites

Active site2741Nucleophile Ref.14
Active site2761Proton donor Ref.14
Metal binding2741Magnesium
Metal binding2761Magnesium; via carbonyl oxygen
Metal binding5021Magnesium

Natural variations

Alternative sequence99 – 12224Missing in isoform 2.
VSP_001490
Alternative sequence401 – 47979Missing in isoform 3.
VSP_001491
Natural variant831P → S.
Corresponds to variant rs2275596 [ dbSNP | Ensembl ].
VAR_048964
Natural variant2381T → A.
Corresponds to variant rs866936 [ dbSNP | Ensembl ].
VAR_048965

Experimental info

Mutagenesis5161P → R: Strongly reduces SIX1 binding. Ref.15
Mutagenesis5321A → R: Abolishes interaction with SIX1. Ref.15
Sequence conflict2961K → E in AAB42065. Ref.7
Sequence conflict3611G → A in AAP35328. Ref.4
Sequence conflict3611G → A in AAH08803. Ref.6
Sequence conflict3811A → S in AAB42065. Ref.7
Sequence conflict4191A → V in CAA07815. Ref.8
Sequence conflict5251D → N in AAB51120. Ref.1

Secondary structure

............................................... 538
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified May 2, 2002. Version 2.
Checksum: 3DBFC31D8BE1E85D

FASTA53859,232
        10         20         30         40         50         60 
MVELVISPSL TVNSDCLDKL KFNRADAAVW TLSDRQGITK SAPLRVSQLF SRSCPRVLPR 

        70         80         90        100        110        120 
QPSTAMAAYG QTQYSAGIQQ ATPYTAYPPP AQAYGIPSYS IKTEDSLNHS PGQSGFLSYG 

       130        140        150        160        170        180 
SSFSTSPTGQ SPYTYQMHGT TGFYQGGNGL GNAAGFGSVH QDYPSYPGFP QSQYPQYYGS 

       190        200        210        220        230        240 
SYNPPYVPAS SICPSPLSTS TYVLQEASHN VPNQSSESLA GEYNTHNGPS TPAKEGDTDR 

       250        260        270        280        290        300 
PHRASDGKLR GRSKRSSDPS PAGDNEIERV FVWDLDETII IFHSLLTGTF ASRYGKDTTT 

       310        320        330        340        350        360 
SVRIGLMMEE MIFNLADTHL FFNDLEDCDQ IHVDDVSSDD NGQDLSTYNF SADGFHSSAP 

       370        380        390        400        410        420 
GANLCLGSGV HGGVDWMRKL AFRYRRVKEM YNTYKNNVGG LIGTPKRETW LQLRAELEAL 

       430        440        450        460        470        480 
TDLWLTHSLK ALNLINSRPN CVNVLVTTTQ LIPALAKVLL YGLGSVFPIE NIYSATKTGK 

       490        500        510        520        530 
ESCFERIMQR FGRKAVYVVI GDGVEEEQGA KKHNMPFWRI SCHADLEALR HALELEYL 

« Hide

Isoform 2 [UniParc].

Checksum: 970E63DB345E484A
Show »

FASTA51456,688
Isoform 3 [UniParc].

Checksum: 774885A6F04CA6B2
Show »

FASTA45950,533

References

« Hide 'large scale' references
[1]"Eyes absent: a gene family found in several metazoan phyla."
Duncan M.K., Kos L., Jenkins N.A., Gilbert D.J., Copeland N.G., Tomarev S.I.
Mamm. Genome 8:479-485(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Embryonic brain.
[2]Erratum
Duncan M.K., Kos L., Jenkins N.A., Gilbert D.J., Copeland N.G., Tomarev S.I.
Mamm. Genome 8:877-877(1997)
[3]"A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family."
Abdelhak S., Kalatzis V., Heilig R., Compain S., Samson D., Vincent C., Weil D., Cruaud C., Sahly I., Leibovici M., Bitner-Glindzicz M., Francis M., Lacombe D., Vigneron J., Charachon R., Boven K., Bedbeder P., van Regemorter N., Weissenbach J., Petit C.
Nat. Genet. 15:157-164(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Tissue: Embryo.
[4]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
[5]"The DNA sequence and comparative analysis of human chromosome 20."
Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. expand/collapse author list , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.
Nature 414:865-871(2001) [PubMed] [Europe PMC] [Abstract]
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 2 AND 3).
Tissue: Lung.
[7]"Cloning and characterization of two vertebrate homologs of the Drosophila eyes absent gene."
Zimmerman J.E., Bui Q.T., Steingrimsson E., Nagle D.L., Fu W., Genin A., Spinner N.B., Copeland N.G., Jenkins N.A., Bucan M., Bonini N.M.
Genome Res. 7:128-141(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 295-538.
Tissue: Brain.
[8]"EYA4, a novel vertebrate gene related to Drosophila eyes absent."
Borsani G., DeGrandi A., Ballabio A., Bulfone A., Bernard L., Banfi S., Gattuso C., Mariani M., Dixon M., Donnai D., Metcalfe K., Winter R., Robertson M., Axton R., Brown A., van Heyningen V., Hanson I.
Hum. Mol. Genet. 8:11-23(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 378-496.
Tissue: Lens epithelium.
[9]"The alpha subunits of Gz and Gi interact with the eyes absent transcription cofactor Eya2, preventing its interaction with the six class of homeodomain-containing proteins."
Fan X., Brass L.F., Poncz M., Spitz F., Maire P., Manning D.R.
J. Biol. Chem. 275:32129-32134(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, INTERACTION WITH GNAZ AND GNAI2.
[10]"Six and Eya expression during human somitogenesis and MyoD gene family activation."
Fougerousse F., Durand M., Lopez S., Suel L., Demignon J., Thornton C., Ozaki H., Kawakami K., Barbet P., Beckmann J.S., Maire P.
J. Muscle Res. Cell Motil. 23:255-264(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, DEVELOPMENTAL STAGE.
[11]"Biochemical and functional characterization of six SIX1 Branchio-oto-renal syndrome mutations."
Patrick A.N., Schiemann B.J., Yang K., Zhao R., Ford H.L.
J. Biol. Chem. 284:20781-20790(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, INTERACTION WITH SIX1.
[12]"Eya2 is required to mediate the pro-metastatic functions of Six1 via the induction of TGF-beta signaling, epithelial-mesenchymal transition, and cancer stem cell properties."
Farabaugh S.M., Micalizzi D.S., Jedlicka P., Zhao R., Ford H.L.
Oncogene 31:552-562(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[13]"Dephosphorylation of the C-terminal tyrosyl residue of the DNA damage-related histone H2A.X is mediated by the protein phosphatase eyes absent."
Krishnan N., Jeong D.G., Jung S.-K., Ryu S.E., Xiao A., Allis C.D., Kim S.J., Tonks N.K.
J. Biol. Chem. 284:16066-16070(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 268-538 IN COMPLEX WITH MAGNESIUM, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES.
[14]"Crystal structure of ED-Eya2: insight into dual roles as a protein tyrosine phosphatase and a transcription factor."
Jung S.K., Jeong D.G., Chung S.J., Kim J.H., Park B.C., Tonks N.K., Ryu S.E., Kim S.J.
FASEB J. 24:560-569(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 268-538 IN COMPLEX WITH MAGNESIUM IONS AND TRANSITION STATE ANALOGS, COFACTOR, ACTIVE SITE.
[15]"Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome."
Patrick A.N., Cabrera J.H., Smith A.L., Chen X.S., Ford H.L., Zhao R.
Nat. Struct. Mol. Biol. 20:447-453(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.99 ANGSTROMS) OF 253-538 IN COMPLEX WITH SIX1, SUBUNIT, MUTAGENESIS OF PRO-516 AND ALA-532.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U71207 mRNA. Translation: AAB51120.1.
Y10261 Genomic DNA. Translation: CAA71310.1.
BT006682 mRNA. Translation: AAP35328.1.
AL049540 expand/collapse EMBL AC list , AL121776, AL359434, AL022342 Genomic DNA. Translation: CAI23166.1.
AL121776 expand/collapse EMBL AC list , AL049540, AL359434, AL022342 Genomic DNA. Translation: CAI42150.1.
AL359434 expand/collapse EMBL AC list , AL049540, AL121776, AL022342 Genomic DNA. Translation: CAI40099.1.
BC000289 mRNA. Translation: AAH00289.2.
BC008803 mRNA. Translation: AAH08803.1.
BC013882 mRNA. Translation: AAH13882.2. Different initiation.
U81601 mRNA. Translation: AAB42065.1.
AJ007992 mRNA. Translation: CAA07815.1.
RefSeqNP_005235.3. NM_005244.4.
NP_742108.2. NM_172110.3.
UniGeneHs.472877.
Hs.722040.
Hs.722415.
Hs.722416.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3GEBX-ray2.40A/B/C/D268-538[»]
3HB0X-ray2.50A/B/C/D268-538[»]
3HB1X-ray2.51A/B/C/D268-538[»]
4EGCX-ray1.99B253-538[»]
ProteinModelPortalO00167.
SMRO00167. Positions 268-538.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108440. 7 interactions.
DIPDIP-40707N.
IntActO00167. 2 interactions.
MINTMINT-139839.

Chemistry

ChEMBLCHEMBL1293275.

PTM databases

PhosphoSiteO00167.

Proteomic databases

PaxDbO00167.
PRIDEO00167.

Protocols and materials databases

DNASU2139.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000327619; ENSP00000333640; ENSG00000064655. [O00167-1]
ENST00000357410; ENSP00000349986; ENSG00000064655. [O00167-3]
GeneID2139.
KEGGhsa:2139.
UCSCuc002xsm.3. human. [O00167-1]
uc010ghp.3. human. [O00167-3]

Organism-specific databases

CTD2139.
GeneCardsGC20P045523.
HGNCHGNC:3520. EYA2.
HPAHPA027024.
MIM601654. gene.
neXtProtNX_O00167.
PharmGKBPA27932.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG297494.
HOVERGENHBG002447.
InParanoidO00167.
KOK17620.
OMAIHSRPNC.
OrthoDBEOG7DNNTZ.
PhylomeDBO00167.
TreeFamTF319337.

Enzyme and pathway databases

SABIO-RKO00167.

Gene expression databases

ArrayExpressO00167.
BgeeO00167.
GenevestigatorO00167.

Family and domain databases

InterProIPR028473. EYA2.
IPR006545. EYA_dom.
IPR028472. EYA_fam.
IPR023214. HAD-like_dom.
[Graphical view]
PANTHERPTHR10190. PTHR10190. 1 hit.
PTHR10190:SF7. PTHR10190:SF7. 1 hit.
SUPFAMSSF56784. SSF56784. 1 hit.
TIGRFAMsTIGR01658. EYA-cons_domain. 1 hit.
ProtoNetSearch...

Other

EvolutionaryTraceO00167.
GeneWikiEYA2.
GenomeRNAi2139.
NextBio8649.
PROO00167.
SOURCESearch...

Entry information

Entry nameEYA2_HUMAN
AccessionPrimary (citable) accession number: O00167
Secondary accession number(s): Q5JSW8 expand/collapse secondary AC list , Q86U84, Q96CV6, Q96H97, Q99503, Q99812, Q9BWF6, Q9H4S3, Q9H4S9, Q9NPZ4, Q9UIX7
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: May 2, 2002
Last modified: April 16, 2014
This is version 135 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 20

Human chromosome 20: entries, gene names and cross-references to MIM