Reviewed, UniProtKB/Swiss-Prot P56975 (NRG3_HUMAN)

Names and origin

Protein names

Recommended name:
    Pro-neuregulin-3, membrane-bound isoform
      Short name=Pro-NRG3
Cleaved into the following chain:
    1- Recommended name:
            Neuregulin-3
                Short name=NRG-3

Gene names

Name:

NRG3

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	720 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Direct ligand for the ERBB4 tyrosine kinase receptor. Binding results in ligand-stimulated tyrosine phosphorylation and activation of the receptor. Does not bind to the EGF receptor, ERBB2 or ERBB3 receptors. May be a survival factor for oligodendrocytes. Ref.1 Ref.2
Subcellular location	Pro-neuregulin-3, membrane-bound isoform: Cell membrane; Single-pass type I membrane protein By similarity. Note: Does not seem to be active By similarity. Neuregulin-3: Secreted By similarity. Isoform 3: Cell membrane; Single-pass type I membrane protein. Note: Isoform 3 is also proteolytically released as a soluble form. Ref.2
Tissue specificity	Highly expressed in most regions of the brain with the exception of corpus callosum. Expressed at lower level in testis. Not detected in heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, ovary, small intestine, colon and peripheral blood leukocytes.
Developmental stage	Isoform 3 is expressed in fetal brain but not in other fetal tissues. Ref.2
Domain	The cytoplasmic domain may be involved in the regulation of trafficking and proteolytic processing. Regulation of the proteolytic processing involves initial intracellular domain dimerization By similarity. ERBB receptor binding is elicited entirely by the EGF-like domain By similarity.
Post-translational modification	Proteolytic cleavage close to the plasma membrane on the external face leads to the release of the soluble growth factor form. Extensive glycosylation precedes the proteolytic cleavage By similarity. Isoform 3 is glycosylated.
Sequence similarities	Belongs to the neuregulin family. Contains 1 EGF-like domain.

Ontologies

Keywords
Cellular component	Cell membrane Membrane Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Domain	EGF-like domain Transmembrane
Molecular function	Growth factor
PTM	Disulfide bond Glycoprotein Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	embryonic development Inferred from electronic annotation. Source: InterPro regulation of cell growth Ref.1 Non-traceable author statement. Source: UniProtKB
Cellular component	extracellular region Ref.1 Non-traceable author statement. Source: UniProtKB integral to plasma membrane Ref.1 Non-traceable author statement. Source: UniProtKB
Molecular function	growth factor activity Ref.1 Non-traceable author statement. Source: UniProtKB receptor tyrosine kinase binding Ref.1 Non-traceable author statement. Source: UniProtKB transmembrane receptor protein tyrosine kinase activator activity Ref.1 Non-traceable author statement. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P56975-1)

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: P56975-2)

The sequence of this isoform differs from the canonical sequence as follows:
     471-477: Missing.

Isoform 3 (identifier: P56975-3)

Also known as: FBNRG3;

The sequence of this isoform differs from the canonical sequence as follows:
     1-221: Missing.
     222-275: PSWPTAAYAT...PETSTSPKFH → MECGIPPTLV...LLLTNSYKFY

Note: Isoform 3 is also proteolytically released as a soluble form. Ref.2

Isoform 4 (identifier: P56975-4)

The sequence of this isoform differs from the canonical sequence as follows:
     529-552: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 720	720	Pro-neuregulin-3, membrane-bound isoform		PRO_0000019481
	Chain	1 – 359	359	Neuregulin-3		PRO_0000019482
Regions
	Topological domain	1 – 360	360	Extracellular Potential
	Transmembrane	361 – 381	21	Internal signal sequence Potential
	Topological domain	382 – 720	339	Cytoplasmic Potential
	Domain	286 – 329	44	EGF-like
	Compositional bias	5 – 8	4	Poly-Ala
	Compositional bias	13 – 21	9	Poly-Ala
	Compositional bias	26 – 34	9	Poly-Ala
	Compositional bias	105 – 285	181	Ser/Thr-rich
	Compositional bias	127 – 135	9	Poly-Thr
	Compositional bias	252 – 260	9	Poly-Ser
	Compositional bias	262 – 265	4	Poly-Thr
Amino acid modifications
	Modified residue	116	1	Phosphoserine Ref.5
	Modified residue	119	1	Phosphoserine Ref.5
	Disulfide bond	290 ↔ 304		By similarity
	Disulfide bond	298 ↔ 317		By similarity
	Disulfide bond	319 ↔ 328		By similarity
Natural variations
	Alternative sequence	1 – 221	221	Missing in isoform 3.		VSP_021828
	Alternative sequence	222 – 275	54	PSWPT…SPKFH → MECGIPPTLVCVGRGGGLHT INIIIWYYFPSAWRTCFNIS SSVGLLLTNSYKFY in isoform 3.		VSP_021829
	Alternative sequence	471 – 477	7	Missing in isoform 2.		VSP_021830
	Alternative sequence	529 – 552	24	Missing in isoform 4.		VSP_035752
	Natural variant	472	1	S → R: dbSNP rs2295934.		VAR_047386
	Natural variant	552	1	K → N: dbSNP rs17101193.		VAR_047387
	Natural variant	576	1	N → K: dbSNP rs17101193.		VAR_057655

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 1, 2000. Version 1. Checksum: A4D6F10DDB95A693	FASTA	720	77,901
	10 20 30 40 50 60 MSEGAAAASP PGAASAAAAS AEEGTAAAAA AAAAGGGPDG GGEGAAEPPR ELRCSDCIVW 70 80 90 100 110 120 NRQQTWLCVV PLFIGFIGLG LSLMLLKWIV VGSVKEYVPT DLVDSKGMGQ DPFFLSKPSS 130 140 150 160 170 180 FPKAMETTTT TTSTTSPATP SAGGAASSRT PNRISTRLTT ITRAPTRFPG HRVPIRASPR 190 200 210 220 230 240 STTARNTAAP ATVPSTTAPF FSSSTLGSRP PVPGTPSTQA MPSWPTAAYA TSSYLHDSTP 250 260 270 280 290 300 SWTLSPFQDA ASSSSSSSSS ATTTTPETST SPKFHTTTYS TERSEHFKPC RDKDLAYCLN 310 320 330 340 350 360 DGECFVIETL TGSHKHCRCK EGYQGVRCDQ FLPKTDSILS DPTDHLGIEF MESEEVYQRQ 370 380 390 400 410 420 VLSISCIIFG IVIVGMFCAA FYFKSKKQAK QIQEQLKVPQ NGKSYSLKAS STMAKSENLV 430 440 450 460 470 480 KSHVQLQNYS KVERHPVTAL EKMMESSFVG PQSFPEVPSP DRGSQSVKHH RSLSSCCSPG 490 500 510 520 530 540 QRSGMLHRNA FRRTPPSPRS RLGGIVGPAY QQLEESRIPD QDTIPCQGIE VRKTISHLPI 550 560 570 580 590 600 QLWCVERPLD LKYSSSGLKT QRNTSINMQL PSRETNPYFN SLEQKDLVGY SSTRASSVPI 610 620 630 640 650 660 IPSVGLEETC LQMPGISEVK SIKWCKNSYS ADVVNVSIPV SDCLIAEQQE VKILLETVQE 670 680 690 700 710 720 QIRILTDARR SEDYELASVE TEDSASENTA FLPLSPTAKS EREAQFVLRN EIQRDSALTK
	Isoform 2. Checksum: 1D5F8D4FA3A138FC	FASTA	713	77,164
	10 20 30 40 50 60 MSEGAAAASP PGAASAAAAS AEEGTAAAAA AAAAGGGPDG GGEGAAEPPR ELRCSDCIVW 70 80 90 100 110 120 NRQQTWLCVV PLFIGFIGLG LSLMLLKWIV VGSVKEYVPT DLVDSKGMGQ DPFFLSKPSS 130 140 150 160 170 180 FPKAMETTTT TTSTTSPATP SAGGAASSRT PNRISTRLTT ITRAPTRFPG HRVPIRASPR 190 200 210 220 230 240 STTARNTAAP ATVPSTTAPF FSSSTLGSRP PVPGTPSTQA MPSWPTAAYA TSSYLHDSTP 250 260 270 280 290 300 SWTLSPFQDA ASSSSSSSSS ATTTTPETST SPKFHTTTYS TERSEHFKPC RDKDLAYCLN 310 320 330 340 350 360 DGECFVIETL TGSHKHCRCK EGYQGVRCDQ FLPKTDSILS DPTDHLGIEF MESEEVYQRQ 370 380 390 400 410 420 VLSISCIIFG IVIVGMFCAA FYFKSKKQAK QIQEQLKVPQ NGKSYSLKAS STMAKSENLV 430 440 450 460 470 480 KSHVQLQNYS KVERHPVTAL EKMMESSFVG PQSFPEVPSP DRGSQSVKHH SPGQRSGMLH 490 500 510 520 530 540 RNAFRRTPPS PRSRLGGIVG PAYQQLEESR IPDQDTIPCQ GIEVRKTISH LPIQLWCVER 550 560 570 580 590 600 PLDLKYSSSG LKTQRNTSIN MQLPSRETNP YFNSLEQKDL VGYSSTRASS VPIIPSVGLE 610 620 630 640 650 660 ETCLQMPGIS EVKSIKWCKN SYSADVVNVS IPVSDCLIAE QQEVKILLET VQEQIRILTD 670 680 690 700 710 ARRSEDYELA SVETEDSASE NTAFLPLSPT AKSEREAQFV LRNEIQRDSA LTK
	Isoform 3 (FBNRG3). Checksum: 6093904545F28F94	FASTA	499	56,034
	10 20 30 40 50 60 MECGIPPTLV CVGRGGGLHT INIIIWYYFP SAWRTCFNIS SSVGLLLTNS YKFYTTTYST 70 80 90 100 110 120 ERSEHFKPCR DKDLAYCLND GECFVIETLT GSHKHCRCKE GYQGVRCDQF LPKTDSILSD 130 140 150 160 170 180 PTDHLGIEFM ESEEVYQRQV LSISCIIFGI VIVGMFCAAF YFKSKKQAKQ IQEQLKVPQN 190 200 210 220 230 240 GKSYSLKASS TMAKSENLVK SHVQLQNYSK VERHPVTALE KMMESSFVGP QSFPEVPSPD 250 260 270 280 290 300 RGSQSVKHHR SLSSCCSPGQ RSGMLHRNAF RRTPPSPRSR LGGIVGPAYQ QLEESRIPDQ 310 320 330 340 350 360 DTIPCQGIEV RKTISHLPIQ LWCVERPLDL KYSSSGLKTQ RNTSINMQLP SRETNPYFNS 370 380 390 400 410 420 LEQKDLVGYS STRASSVPII PSVGLEETCL QMPGISEVKS IKWCKNSYSA DVVNVSIPVS 430 440 450 460 470 480 DCLIAEQQEV KILLETVQEQ IRILTDARRS EDYELASVET EDSASENTAF LPLSPTAKSE 490 REAQFVLRNE IQRDSALTK
	Isoform 4. Checksum: 1823F048DB30043C	FASTA	696	75,031
	10 20 30 40 50 60 MSEGAAAASP PGAASAAAAS AEEGTAAAAA AAAAGGGPDG GGEGAAEPPR ELRCSDCIVW 70 80 90 100 110 120 NRQQTWLCVV PLFIGFIGLG LSLMLLKWIV VGSVKEYVPT DLVDSKGMGQ DPFFLSKPSS 130 140 150 160 170 180 FPKAMETTTT TTSTTSPATP SAGGAASSRT PNRISTRLTT ITRAPTRFPG HRVPIRASPR 190 200 210 220 230 240 STTARNTAAP ATVPSTTAPF FSSSTLGSRP PVPGTPSTQA MPSWPTAAYA TSSYLHDSTP 250 260 270 280 290 300 SWTLSPFQDA ASSSSSSSSS ATTTTPETST SPKFHTTTYS TERSEHFKPC RDKDLAYCLN 310 320 330 340 350 360 DGECFVIETL TGSHKHCRCK EGYQGVRCDQ FLPKTDSILS DPTDHLGIEF MESEEVYQRQ 370 380 390 400 410 420 VLSISCIIFG IVIVGMFCAA FYFKSKKQAK QIQEQLKVPQ NGKSYSLKAS STMAKSENLV 430 440 450 460 470 480 KSHVQLQNYS KVERHPVTAL EKMMESSFVG PQSFPEVPSP DRGSQSVKHH RSLSSCCSPG 490 500 510 520 530 540 QRSGMLHRNA FRRTPPSPRS RLGGIVGPAY QQLEESRIPD QDTIPCQGYS SSGLKTQRNT 550 560 570 580 590 600 SINMQLPSRE TNPYFNSLEQ KDLVGYSSTR ASSVPIIPSV GLEETCLQMP GISEVKSIKW 610 620 630 640 650 660 CKNSYSADVV NVSIPVSDCL IAEQQEVKIL LETVQEQIRI LTDARRSEDY ELASVETEDS 670 680 690 ASENTAFLPL SPTAKSEREA QFVLRNEIQR DSALTK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4." Zhang D., Sliwkowski M.X., Mark M., Frantz G., Akita R., Sun Y., Hillan K., Crowley C., Brush J., Godowski P.J. Proc. Natl. Acad. Sci. U.S.A. 94:9562-9567(1997) [PubMed: 9275162] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION. Tissue: Fetal brain.
[2]	"Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival." Carteron C., Ferrer-Montiel A.V., Cabedo H. J. Cell Sci. 119:898-909(2006) [PubMed: 16478787] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), DEVELOPMENTAL STAGE, SUBCELLULAR LOCATION, GLYCOSYLATION, FUNCTION. Tissue: Fetal brain.
[3]	"Bi-directional signalling by NRG-3 cytoplasmic domain." Tiao J.Y., Busfield S.J. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
[4]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed: 15164054] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column." Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y. Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-116 AND SER-119, MASS SPECTROMETRY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	DQ857894 mRNA. Translation: ABG77979.1. DQ001411 mRNA. Translation: AAY17216.1. AL354749 , AL096706, AL136085, AL391478, AL513204, AL589782 Genomic DNA. Translation: CAH70641.1. AL136085 , AL096706, AL354749, AL391478, AL513204, AL589782 Genomic DNA. Translation: CAH71050.1. AL513204 , AL096706, AL136085, AL354749, AL391478, AL589782 Genomic DNA. Translation: CAH73645.1. AL391478 , AL096706, AL136085, AL354749, AL513204, AL589782 Genomic DNA. Translation: CAI15622.1. AL589782 , AL096706, AL136085, AL354749, AL391478, AL513204 Genomic DNA. Translation: CAI17213.1. AL096706 , AL136085, AL354749, AL391478, AL513204, AL589782 Genomic DNA. Translation: CAI22410.1.
IPI	IPI00012044. IPI00749451. IPI00807378. IPI00914901.
RefSeq	NP_001010848.2.
UniGene	Hs.125119
3D structure databases
HSSP	HSSP built from PDB template 1JL9 based on UniProtKB P01133.
ModBase	Search...
Protein-protein interaction databases
STRING	P56975.
PTM databases
PhosphoSite	P56975.
Proteomic databases
PRIDE	P56975.
Genome annotation databases
Ensembl	ENST00000372141; ENSP00000361214; ENSG00000185737; Homo sapiens. [Genome view] ENST00000372142; ENSP00000361215; ENSG00000185737; Homo sapiens. [Genome view] ENST00000404547; ENSP00000384796; ENSG00000185737; Homo sapiens. [Genome view] ENST00000404576; ENSP00000385804; ENSG00000185737; Homo sapiens. [Genome view]
GeneID	10718.
KEGG	hsa:10718.
UCSC	uc001kco.1. human. uc001kcp.1. human.
Organism-specific databases
GeneCards	GC10P083625.
HGNC	HGNC:7999. NRG3.
MIM	605533. gene.
PharmGKB	PA31778.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P56975.
HOVERGEN	P56975.
Gene expression databases
ArrayExpress	P56975.
Bgee	P56975.
CleanEx	HS_NRG3.
Genevestigator	P56975.
GermOnline	ENSG00000185737. Homo sapiens.
Family and domain databases
InterPro	IPR006209. EGF. IPR006210. EGF-like. IPR013032. EGF-like_reg_CS. IPR000742. EGF_3. IPR002154. Neuregulin_1_C. [Graphical view]
Pfam	PF00008. EGF. 1 hit. PF02158. Neuregulin. 1 hit. [Graphical view]
SMART	SM00181. EGF. 1 hit. [Graphical view]
PROSITE	PS00022. EGF_1. 1 hit. PS01186. EGF_2. 1 hit. PS50026. EGF_3. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
SOURCE	Search...

Entry information

Entry name

NRG3_HUMAN

Accession

Primary (citable) accession number: P56975
Secondary accession number(s): A4D7U1, Q0PEH2, Q5VYH3

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	December 1, 2000
Last modified:	October 13, 2009
This is version 78 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.