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Protein

Pro-neuregulin-3, membrane-bound isoform

Gene

NRG3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.2 Publications

GO - Molecular functioni

  • growth factor activity Source: UniProtKB
  • receptor binding Source: GO_Central
  • receptor tyrosine kinase binding Source: UniProtKB
  • transmembrane receptor protein tyrosine kinase activator activity Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Growth factor

Enzyme and pathway databases

ReactomeiREACT_115596. Signaling by ERBB4.
REACT_115755. Signaling by ERBB2.
REACT_115854. GRB2 events in ERBB2 signaling.
REACT_115961. PI3K events in ERBB4 signaling.
REACT_115993. SHC1 events in ERBB2 signaling.
REACT_116005. SHC1 events in ERBB4 signaling.
REACT_116008. PI3K events in ERBB2 signaling.
REACT_116022. Nuclear signaling by ERBB4.
REACT_147727. Constitutive Signaling by Aberrant PI3K in Cancer.
REACT_75829. PIP3 activates AKT signaling.
SignaLinkiP56975.

Names & Taxonomyi

Protein namesi
Recommended name:
Pro-neuregulin-3, membrane-bound isoform
Short name:
Pro-NRG3
Cleaved into the following chain:
Neuregulin-3
Short name:
NRG-3
Gene namesi
Name:NRG3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 10

Organism-specific databases

HGNCiHGNC:7999. NRG3.

Subcellular locationi

Pro-neuregulin-3, membrane-bound isoform :
Neuregulin-3 :
Isoform 3 :

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 360360ExtracellularSequence AnalysisAdd
BLAST
Transmembranei361 – 38121Helical; Note=Internal signal sequenceSequence AnalysisAdd
BLAST
Topological domaini382 – 720339CytoplasmicSequence AnalysisAdd
BLAST

GO - Cellular componenti

  • extracellular region Source: UniProtKB
  • extracellular space Source: GO_Central
  • integral component of plasma membrane Source: UniProtKB
  • intracellular Source: GOC
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA31778.

Polymorphism and mutation databases

BioMutaiNRG3.
DMDMi9789758.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 720720Pro-neuregulin-3, membrane-bound isoformPRO_0000019481Add
BLAST
Chaini1 – 359359Neuregulin-3PRO_0000019482Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi290 ↔ 304PROSITE-ProRule annotation
Disulfide bondi298 ↔ 317PROSITE-ProRule annotation
Disulfide bondi319 ↔ 328PROSITE-ProRule annotation

Post-translational modificationi

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.By similarity1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiP56975.
PRIDEiP56975.

PTM databases

PhosphoSiteiP56975.

Expressioni

Tissue specificityi

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 stagei

Isoform 3 is expressed in fetal brain but not in other fetal tissues.1 Publication

Gene expression databases

BgeeiP56975.
CleanExiHS_NRG3.
ExpressionAtlasiP56975. baseline and differential.
GenevisibleiP56975. HS.

Interactioni

Subunit structurei

Interacts with ERBB4.1 Publication

Protein-protein interaction databases

STRINGi9606.ENSP00000361214.

Structurei

3D structure databases

ProteinModelPortaliP56975.
SMRiP56975. Positions 286-333.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini286 – 32944EGF-likePROSITE-ProRule annotationAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi5 – 84Poly-Ala
Compositional biasi13 – 219Poly-Ala
Compositional biasi26 – 349Poly-Ala
Compositional biasi105 – 285181Ser/Thr-richAdd
BLAST
Compositional biasi127 – 1359Poly-Thr
Compositional biasi252 – 2609Poly-Ser
Compositional biasi262 – 2654Poly-Thr

Domaini

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).By similarity
ERBB receptor binding is elicited entirely by the EGF-like domain.By similarity

Sequence similaritiesi

Belongs to the neuregulin family.Curated
Contains 1 EGF-like domain.PROSITE-ProRule annotation

Keywords - Domaini

EGF-like domain, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG40523.
GeneTreeiENSGT00800000124099.
HOGENOMiHOG000113852.
HOVERGENiHBG006532.
InParanoidiP56975.
KOiK05457.
OrthoDBiEOG7SR4KZ.
PhylomeDBiP56975.
TreeFamiTF336537.

Family and domain databases

InterProiIPR000742. EG-like_dom.
IPR013032. EGF-like_CS.
[Graphical view]
SMARTiSM00181. EGF. 1 hit.
[Graphical view]
PROSITEiPS00022. EGF_1. 1 hit.
PS01186. EGF_2. 1 hit.
PS50026. EGF_3. 1 hit.
[Graphical view]

Sequences (4)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P56975-1) [UniParc]FASTAAdd to basket

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

        10         20         30         40         50
MSEGAAAASP PGAASAAAAS AEEGTAAAAA AAAAGGGPDG GGEGAAEPPR
60 70 80 90 100
ELRCSDCIVW NRQQTWLCVV PLFIGFIGLG LSLMLLKWIV VGSVKEYVPT
110 120 130 140 150
DLVDSKGMGQ DPFFLSKPSS FPKAMETTTT TTSTTSPATP SAGGAASSRT
160 170 180 190 200
PNRISTRLTT ITRAPTRFPG HRVPIRASPR STTARNTAAP ATVPSTTAPF
210 220 230 240 250
FSSSTLGSRP PVPGTPSTQA MPSWPTAAYA TSSYLHDSTP SWTLSPFQDA
260 270 280 290 300
ASSSSSSSSS ATTTTPETST SPKFHTTTYS TERSEHFKPC RDKDLAYCLN
310 320 330 340 350
DGECFVIETL TGSHKHCRCK EGYQGVRCDQ FLPKTDSILS DPTDHLGIEF
360 370 380 390 400
MESEEVYQRQ VLSISCIIFG IVIVGMFCAA FYFKSKKQAK QIQEQLKVPQ
410 420 430 440 450
NGKSYSLKAS STMAKSENLV KSHVQLQNYS KVERHPVTAL EKMMESSFVG
460 470 480 490 500
PQSFPEVPSP DRGSQSVKHH RSLSSCCSPG QRSGMLHRNA FRRTPPSPRS
510 520 530 540 550
RLGGIVGPAY QQLEESRIPD QDTIPCQGIE VRKTISHLPI QLWCVERPLD
560 570 580 590 600
LKYSSSGLKT QRNTSINMQL PSRETNPYFN SLEQKDLVGY SSTRASSVPI
610 620 630 640 650
IPSVGLEETC LQMPGISEVK SIKWCKNSYS ADVVNVSIPV SDCLIAEQQE
660 670 680 690 700
VKILLETVQE QIRILTDARR SEDYELASVE TEDSASENTA FLPLSPTAKS
710 720
EREAQFVLRN EIQRDSALTK
Length:720
Mass (Da):77,901
Last modified:December 1, 2000 - v1
Checksum:iA4D6F10DDB95A693
GO
Isoform 2 (identifier: P56975-2) [UniParc]FASTAAdd to basket

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

Show »
Length:713
Mass (Da):77,164
Checksum:i1D5F8D4FA3A138FC
GO
Isoform 3 (identifier: P56975-3) [UniParc]FASTAAdd to basket

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

Show »
Length:499
Mass (Da):56,034
Checksum:i6093904545F28F94
GO
Isoform 4 (identifier: P56975-4) [UniParc]FASTAAdd to basket

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

Show »
Length:696
Mass (Da):75,031
Checksum:i1823F048DB30043C
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti472 – 4721S → R.
Corresponds to variant rs2295934 [ dbSNP | Ensembl ].
VAR_047386
Natural varianti552 – 5521K → N.
Corresponds to variant rs17101193 [ dbSNP | Ensembl ].
VAR_047387

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 221221Missing in isoform 3. 1 PublicationVSP_021828Add
BLAST
Alternative sequencei222 – 27554PSWPT…SPKFH → MECGIPPTLVCVGRGGGLHT INIIIWYYFPSAWRTCFNIS SSVGLLLTNSYKFY in isoform 3. 1 PublicationVSP_021829Add
BLAST
Alternative sequencei471 – 4777Missing in isoform 2. CuratedVSP_021830
Alternative sequencei529 – 55224Missing in isoform 4. 1 PublicationVSP_035752Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS31233.1. [P56975-4]
CCDS53547.1. [P56975-3]
RefSeqiNP_001010848.2. NM_001010848.3. [P56975-4]
NP_001159445.1. NM_001165973.1. [P56975-3]
XP_005269501.1. XM_005269444.3. [P56975-1]
UniGeneiHs.125119.

Genome annotation databases

EnsembliENST00000372141; ENSP00000361214; ENSG00000185737. [P56975-4]
ENST00000372142; ENSP00000361215; ENSG00000185737. [P56975-3]
ENST00000404547; ENSP00000384796; ENSG00000185737.
GeneIDi10718.
KEGGihsa:10718.
UCSCiuc001kco.2. human. [P56975-4]
uc001kcp.2. human. [P56975-3]
uc001kcr.2. human. [P56975-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS31233.1. [P56975-4]
CCDS53547.1. [P56975-3]
RefSeqiNP_001010848.2. NM_001010848.3. [P56975-4]
NP_001159445.1. NM_001165973.1. [P56975-3]
XP_005269501.1. XM_005269444.3. [P56975-1]
UniGeneiHs.125119.

3D structure databases

ProteinModelPortaliP56975.
SMRiP56975. Positions 286-333.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9606.ENSP00000361214.

PTM databases

PhosphoSiteiP56975.

Polymorphism and mutation databases

BioMutaiNRG3.
DMDMi9789758.

Proteomic databases

PaxDbiP56975.
PRIDEiP56975.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000372141; ENSP00000361214; ENSG00000185737. [P56975-4]
ENST00000372142; ENSP00000361215; ENSG00000185737. [P56975-3]
ENST00000404547; ENSP00000384796; ENSG00000185737.
GeneIDi10718.
KEGGihsa:10718.
UCSCiuc001kco.2. human. [P56975-4]
uc001kcp.2. human. [P56975-3]
uc001kcr.2. human. [P56975-1]

Organism-specific databases

CTDi10718.
GeneCardsiGC10P083625.
HGNCiHGNC:7999. NRG3.
MIMi605533. gene.
neXtProtiNX_P56975.
PharmGKBiPA31778.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG40523.
GeneTreeiENSGT00800000124099.
HOGENOMiHOG000113852.
HOVERGENiHBG006532.
InParanoidiP56975.
KOiK05457.
OrthoDBiEOG7SR4KZ.
PhylomeDBiP56975.
TreeFamiTF336537.

Enzyme and pathway databases

ReactomeiREACT_115596. Signaling by ERBB4.
REACT_115755. Signaling by ERBB2.
REACT_115854. GRB2 events in ERBB2 signaling.
REACT_115961. PI3K events in ERBB4 signaling.
REACT_115993. SHC1 events in ERBB2 signaling.
REACT_116005. SHC1 events in ERBB4 signaling.
REACT_116008. PI3K events in ERBB2 signaling.
REACT_116022. Nuclear signaling by ERBB4.
REACT_147727. Constitutive Signaling by Aberrant PI3K in Cancer.
REACT_75829. PIP3 activates AKT signaling.
SignaLinkiP56975.

Miscellaneous databases

ChiTaRSiNRG3. human.
GeneWikiiNRG3.
GenomeRNAii10718.
NextBioi40693.
PROiP56975.
SOURCEiSearch...

Gene expression databases

BgeeiP56975.
CleanExiHS_NRG3.
ExpressionAtlasiP56975. baseline and differential.
GenevisibleiP56975. HS.

Family and domain databases

InterProiIPR000742. EG-like_dom.
IPR013032. EGF-like_CS.
[Graphical view]
SMARTiSM00181. EGF. 1 hit.
[Graphical view]
PROSITEiPS00022. EGF_1. 1 hit.
PS01186. EGF_2. 1 hit.
PS50026. EGF_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  5. "Ligand discrimination in signaling through an ErbB4 receptor homodimer."
    Sweeney C., Lai C., Riese D.J. II, Diamonti A.J., Cantley L.C., Carraway K.L. III
    J. Biol. Chem. 275:19803-19807(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH ERBB4.

Entry informationi

Entry nameiNRG3_HUMAN
AccessioniPrimary (citable) accession number: P56975
Secondary accession number(s): A4D7U1, Q0PEH2, Q5VYH3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: December 1, 2000
Last modified: July 22, 2015
This is version 132 of the entry and version 1 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

Complete proteome, Reference proteome

Documents

  1. Human chromosome 10
    Human chromosome 10: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.