Q9UBP5 (HEY2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Hairy/enhancer-of-split related with YRPW motif protein 2

Alternative name(s):
Cardiovascular helix-loop-helix factor 1
Short name=hCHF1
Class B basic helix-loop-helix protein 32
Short name=bHLHb32
HES-related repressor protein 2
Hairy and enhancer of split-related protein 2
Short name=HESR-2
Hairy-related transcription factor 2
Short name=HRT-2
Short name=hHRT2
Protein gridlock homolog

Gene names

Name:	HEY2
Synonyms:	BHLHB32, CHF1, GRL, HERP, HERP1, HRT2

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	337 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Downstream effector of Notch signaling which may be required for cardiovascular development. Transcriptional repressor which binds preferentially to the canonical E box sequence 5'-CACGTG-3'. Represses transcription by the cardiac transcriptional activators GATA4 and GATA6. Ref.3 Ref.4 Ref.10 Ref.11
Subunit structure	May self-associate By similarity. Interacts with GATA4, HES1 and HEYL By similarity. Interacts with HDAC1, NCOR1 and SIN3A By similarity. Interacts with ARNT and GATA6. Ref.3 Ref.11
Subcellular location	Nucleus By similarity.
Sequence similarities	Belongs to the HEY family. Contains 1 bHLH (basic helix-loop-helix) domain. Contains 1 Orange domain.

Ontologies

Keywords
Biological process	Notch signaling pathway Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Ligand	DNA-binding
Molecular function	Developmental protein Repressor
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Notch signaling involved in heart development Inferred by curator PubMed 12372254. Source: BHF-UCL anterior/posterior axis specification Inferred from electronic annotation. Source: Compara arterial endothelial cell differentiation Inferred from sequence or structural similarity. Source: BHF-UCL ascending aorta morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL atrial septum morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL atrioventricular valve development Inferred from electronic annotation. Source: Compara cardiac epithelial to mesenchymal transition Inferred from sequence or structural similarity. Source: BHF-UCL cardiac left ventricle morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL cardiac muscle hypertrophy in response to stress Inferred from electronic annotation. Source: Compara cardiac right ventricle morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL cardiac vascular smooth muscle cell development Inferred from electronic annotation. Source: Compara cell fate commitment Inferred from electronic annotation. Source: Compara cochlea development Inferred from electronic annotation. Source: Compara coronary vasculature morphogenesis Inferred from electronic annotation. Source: Compara dorsal aorta morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL endocardial cushion to mesenchymal transition involved in heart valve formation Inferred from electronic annotation. Source: Compara heart trabecula formation Inferred from electronic annotation. Source: Compara labyrinthine layer blood vessel development Inferred from sequence or structural similarity. Source: BHF-UCL muscular septum morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of Notch signaling pathway Inferred from electronic annotation. Source: Compara negative regulation of cardiac muscle cell apoptotic process Inferred from electronic annotation. Source: Compara negative regulation of cardiac vascular smooth muscle cell differentiation Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of transcription by transcription factor localization Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of transcription from RNA polymerase II promoter involved in smooth muscle cell differentiation Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of transcription initiation from RNA polymerase II promoter Inferred from direct assay Ref.3. Source: BHF-UCL negative regulation of transcription regulatory region DNA binding Inferred from direct assay Ref.3. Source: BHF-UCL outflow tract morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of cardiac muscle cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of heart rate Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from sequence or structural similarity. Source: BHF-UCL protein-DNA complex assembly Inferred from electronic annotation. Source: Compara pulmonary artery morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL pulmonary valve morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL regulation of auditory receptor cell differentiation Inferred from electronic annotation. Source: Compara regulation of vasculogenesis Inferred from sequence or structural similarity. Source: BHF-UCL tricuspid valve formation Inferred from electronic annotation. Source: Compara tricuspid valve morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL umbilical cord morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL vascular smooth muscle cell development Inferred from expression pattern PubMed 15821257. Source: UniProtKB vasculogenesis Inferred from electronic annotation. Source: Compara ventricular cardiac muscle cell development Inferred from sequence or structural similarity. Source: UniProtKB ventricular trabecula myocardium morphogenesis Inferred from electronic annotation. Source: Compara
Cellular_component	cytoplasm Inferred from sequence or structural similarity. Source: UniProtKB transcriptional repressor complex Inferred from direct assay PubMed 11486045. Source: BHF-UCL
Molecular_function	RNA polymerase II core promoter sequence-specific DNA binding transcription factor activity Inferred from sequence or structural similarity. Source: UniProtKB microsatellite binding Inferred from direct assay PubMed 21290414. Source: UniProtKB protein binding transcription factor activity Inferred from direct assay PubMed 21290414. Source: UniProtKB transcription factor binding Non-traceable author statement PubMed 17611704. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
HTT	P42858	2	EBI-750630,EBI-466029
SIRT1	Q96EB6	3	EBI-750630,EBI-1802965

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 337	337	Hairy/enhancer-of-split related with YRPW motif protein 2		PRO_0000245515
Regions
	Domain	48 – 103	56	bHLH
	Domain	122 – 157	36	Orange
	Region	47 – 116	70	Transcriptional repression and interaction with NCOR1 and SIN3A By similarity
	Motif	327 – 330	4	YRPW motif
	Compositional bias	175 – 191	17	His-rich
	Compositional bias	262 – 302	41	Ala-rich
Natural variations
	Natural variant	96	1	T → A in a patient with atrioventricular septal defects. Ref.12		VAR_026974
	Natural variant	98	1	D → A in a patient with atrioventricular septal defects. Ref.12		VAR_026975
	Natural variant	100	1	L → S in a patient with atrioventricular septal defects. Ref.12		VAR_026976
	Natural variant	140	1	V → M. Corresponds to variant rs3734638 [ dbSNP | Ensembl ].		VAR_026977
Experimental info
	Mutagenesis	54	1	G → P: Impairs transcriptional repression. Ref.11

Sequences

	Sequence		Length	Mass (Da)
	Q9UBP5 [UniParc]. Last modified May 1, 2000. Version 1. Checksum: 71B7B1AA69BA88D2	FASTA	337	35,808
	10 20 30 40 50 60 MKRPCEETTS ESDMDETIDV GSENNYSGQS TSSVIRLNSP TTTSQIMARK KRRGIIEKRR 70 80 90 100 110 120 RDRINNSLSE LRRLVPTAFE KQGSAKLEKA EILQMTVDHL KMLQATGGKG YFDAHALAMD 130 140 150 160 170 180 FMSIGFRECL TEVARYLSSV EGLDSSDPLR VRLVSHLSTC ATQREAAAMT SSMAHHHHPL 190 200 210 220 230 240 HPHHWAAAFH HLPAALLQPN GLHASESTPC RLSTTSEVPP AHGSALLTAT FAHADSALRM 250 260 270 280 290 300 PSTGSVAPCV PPLSTSLLSL SATVHAAAAA ATAAAHSFPL SFAGAFPMLP PNAAAAVAAA 310 320 330 TAISPPLSVS ATSSPQQTSS GTNNKPYRPW GTEVGAF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Hey genes: a novel subfamily of hairy- and enhancer of split related genes specifically expressed during mouse embryogenesis." Leimeister C., Externbrinck A., Klamt B., Gessler M. Mech. Dev. 85:173-177(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Gridlock, an HLH gene required for assembly of the aorta in zebrafish." Zhong T.P., Rosenberg M., Mohideen M.-A.P.K., Weinstein B., Fishman M.C. Science 287:1820-1824(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Heart.
[3]	"Cardiovascular basic helix loop helix factor 1, a novel transcriptional repressor expressed preferentially in the developing and adult cardiovascular system." Chin M.T., Maemura K., Fukumoto S., Jain M.K., Layne M.D., Watanabe M., Hsieh C.-M., Lee M.-E. J. Biol. Chem. 275:6381-6387(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH ARNT. Tissue: Heart.
[4]	"Members of the HRT family of basic helix-loop-helix proteins act as transcriptional repressors downstream of Notch signaling." Nakagawa O., McFadden D.G., Nakagawa M., Yanagisawa H., Hu T., Srivastava D., Olson E.N. Proc. Natl. Acad. Sci. U.S.A. 97:13655-13660(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, DNA-BINDING.
[5]	"HERP, a new primary target of Notch regulated by ligand binding." Iso T., Sartorelli V., Chung G., Shichinohe T., Kedes L., Hamamori Y. Mol. Cell. Biol. 21:6071-6079(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Heart.
[6]	"Homo sapiens testis cDNA clone, basic-helix-loop-helix protein (Hey2)." Tanaka K., Miyata J., Ikeda J. Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Testis.
[7]	"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 (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[8]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	"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]. Tissue: Lung.
[10]	"Hairy-related transcription factors inhibit GATA-dependent cardiac gene expression through a signal-responsive mechanism." Kathiriya I.S., King I.N., Murakami M., Nakagawa M., Astle J.M., Gardner K.A., Gerard R.D., Olson E.N., Srivastava D., Nakagawa O. J. Biol. Chem. 279:54937-54943(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[11]	"CHF1/Hey2 suppresses SM-MHC promoter activity through an interaction with GATA-6." Shirvani S., Xiang F., Koibuchi N., Chin M.T. Biochem. Biophys. Res. Commun. 339:151-156(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH GATA6, MUTAGENESIS OF GLY-54.
[12]	"HEY2 mutations in malformed hearts." Reamon-Buettner S.M., Borlak J. Hum. Mutat. 27:118-118(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS ALA-96; ALA-98 AND SER-100.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AJ249545 mRNA. Translation: CAB56839.1. AF237949 mRNA. Translation: AAF44781.1. AF173901 mRNA. Translation: AAF20173.1. AF311884 mRNA. Translation: AAG31157.1. AF232238 mRNA. Translation: AAF37296.1. AB044755 mRNA. Translation: BAA96781.1. BT020067 mRNA. Translation: AAV38870.1. BT020068 mRNA. Translation: AAV38871.1. AL078594 Genomic DNA. Translation: CAB87581.1. BC007707 mRNA. Translation: AAH07707.1.
IPI	IPI00016845.
RefSeq	NP_036391.1. NM_012259.2.
UniGene	Hs.144287.
3D structure databases
ProteinModelPortal	Q9UBP5.
SMR	Q9UBP5. Positions 56-107, 110-164.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9UBP5. 5 interactions.
MINT	MINT-1469894.
STRING	9606.ENSP00000357348.
PTM databases
PhosphoSite	Q9UBP5.
Polymorphism databases
DMDM	74762767.
Proteomic databases
PaxDb	Q9UBP5.
PRIDE	Q9UBP5.
Protocols and materials databases
DNASU	23493.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000368364; ENSP00000357348; ENSG00000135547.
GeneID	23493.
KEGG	hsa:23493.
UCSC	uc003qad.3. human.
Organism-specific databases
CTD	23493.
GeneCards	GC06P126068.
HGNC	HGNC:4881. HEY2.
HPA	HPA030205.
MIM	604674. gene.
neXtProt	NX_Q9UBP5.
PharmGKB	PA29259.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG324798.
HOGENOM	HOG000286035.
HOVERGEN	HBG003275.
InParanoid	Q9UBP5.
KO	K09091.
OMA	TCASQRE.
OrthoDB	EOG4GB77H.
PhylomeDB	Q9UBP5.
Enzyme and pathway databases
Reactome	REACT_111102. Signal Transduction.
Gene expression databases
ArrayExpress	Q9UBP5.
Bgee	Q9UBP5.
CleanEx	HS_HEY2.
Genevestigator	Q9UBP5.
GermOnline	ENSG00000135547. Homo sapiens.
Family and domain databases
Gene3D	4.10.280.10. 1 hit.
InterPro	IPR011598. bHLH_dom. IPR003650. Orange. IPR018352. Orange_subgr. [Graphical view]
Pfam	PF07527. Hairy_orange. 1 hit. PF00010. HLH. 1 hit. [Graphical view]
SMART	SM00353. HLH. 1 hit. SM00511. ORANGE. 1 hit. [Graphical view]
SUPFAM	SSF47459. HLH_basic. 1 hit.
PROSITE	PS50888. BHLH. 1 hit. PS51054. ORANGE. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	23493.
NextBio	45859.
SOURCE	Search...

Entry information

Entry name

HEY2_HUMAN

Accession

Primary (citable) accession number: Q9UBP5

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 11, 2006
Last sequence update:	May 1, 2000
Last modified:	May 1, 2013
This is version 106 of the entry and version 1 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.