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Protein

Pro-neuregulin-3, membrane-bound isoform

Gene

NRG3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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

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

GO - Biological processi

Keywordsi

Molecular functionGrowth factor

Enzyme and pathway databases

ReactomeiR-HSA-1227986 Signaling by ERBB2
R-HSA-1236394 Signaling by ERBB4
R-HSA-1250196 SHC1 events in ERBB2 signaling
R-HSA-1250342 PI3K events in ERBB4 signaling
R-HSA-1250347 SHC1 events in ERBB4 signaling
R-HSA-1251985 Nuclear signaling by ERBB4
R-HSA-1257604 PIP3 activates AKT signaling
R-HSA-1963640 GRB2 events in ERBB2 signaling
R-HSA-1963642 PI3K events in ERBB2 signaling
R-HSA-2219530 Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5673001 RAF/MAP kinase cascade
R-HSA-6785631 ERBB2 Regulates Cell Motility
R-HSA-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8847993 ERBB2 Activates PTK6 Signaling
R-HSA-8863795 Downregulation of ERBB2 signaling
SignaLinkiP56975
SIGNORiP56975

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
Proteomesi
  • UP000005640 Componenti: Chromosome 10

Organism-specific databases

EuPathDBiHostDB:ENSG00000185737.12
HGNCiHGNC:7999 NRG3
MIMi605533 gene
neXtProtiNX_P56975

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 360ExtracellularSequence analysisAdd BLAST360
Transmembranei361 – 381Helical; Note=Internal signal sequenceSequence analysisAdd BLAST21
Topological domaini382 – 720CytoplasmicSequence analysisAdd BLAST339

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Organism-specific databases

DisGeNETi10718
OpenTargetsiENSG00000185737
PharmGKBiPA31778

Polymorphism and mutation databases

BioMutaiNRG3
DMDMi9789758

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000194811 – 720Pro-neuregulin-3, membrane-bound isoformAdd BLAST720
ChainiPRO_00000194821 – 359Neuregulin-3Add BLAST359

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
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
PeptideAtlasiP56975
PRIDEiP56975

PTM databases

iPTMnetiP56975
PhosphoSitePlusiP56975

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

BgeeiENSG00000185737
CleanExiHS_NRG3
ExpressionAtlasiP56975 baseline and differential
GenevisibleiP56975 HS

Interactioni

Subunit structurei

Interacts with ERBB4.1 Publication

GO - Molecular functioni

  • chemorepellent activity Source: Ensembl
  • growth factor activity Source: UniProtKB
  • receptor tyrosine kinase binding Source: UniProtKB
  • signaling receptor binding Source: GO_Central

Protein-protein interaction databases

STRINGi9606.ENSP00000361214

Structurei

3D structure databases

ProteinModelPortaliP56975
SMRiP56975
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini286 – 329EGF-likePROSITE-ProRule annotationAdd BLAST44

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi5 – 8Poly-Ala4
Compositional biasi13 – 21Poly-Ala9
Compositional biasi26 – 34Poly-Ala9
Compositional biasi105 – 285Ser/Thr-richAdd BLAST181
Compositional biasi127 – 135Poly-Thr9
Compositional biasi252 – 260Poly-Ser9
Compositional biasi262 – 265Poly-Thr4

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

Keywords - Domaini

EGF-like domain, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IMQB Eukaryota
ENOG4111KAZ LUCA
GeneTreeiENSGT00900000140940
HOGENOMiHOG000113852
HOVERGENiHBG006532
InParanoidiP56975
KOiK05457
OrthoDBiEOG091G07O8
PhylomeDBiP56975
TreeFamiTF336537

Family and domain databases

InterProiView protein in InterPro
IPR013032 EGF-like_CS
IPR000742 EGF-like_dom
IPR002154 Neuregulin_C
PfamiView protein in Pfam
PF02158 Neuregulin, 1 hit
PROSITEiView protein in PROSITE
PS00022 EGF_1, 1 hit
PS01186 EGF_2, 1 hit
PS50026 EGF_3, 1 hit

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)DescriptionActionsGraphical viewLength
Natural variantiVAR_047386472S → R. Corresponds to variant dbSNP:rs2295934Ensembl.1
Natural variantiVAR_047387552K → N. Corresponds to variant dbSNP:rs17101193Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0218281 – 221Missing in isoform 3. 1 PublicationAdd BLAST221
Alternative sequenceiVSP_021829222 – 275PSWPT…SPKFH → MECGIPPTLVCVGRGGGLHT INIIIWYYFPSAWRTCFNIS SSVGLLLTNSYKFY in isoform 3. 1 PublicationAdd BLAST54
Alternative sequenceiVSP_021830471 – 477Missing in isoform 2. Curated7
Alternative sequenceiVSP_035752529 – 552Missing in isoform 4. 1 PublicationAdd BLAST24

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
DQ857894 mRNA Translation: ABG77979.1
DQ001411 mRNA Translation: AAY17216.1
AL096706 Genomic DNA No translation available.
AL136085 Genomic DNA No translation available.
AL354749 Genomic DNA No translation available.
AL391478 Genomic DNA No translation available.
AL513204 Genomic DNA No translation available.
AL589782 Genomic DNA No translation available.
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_005269444.4 [P56975-1]
UniGeneiHs.125119

Genome annotation databases

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

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiNRG3_HUMAN
AccessioniPrimary (citable) accession number: P56975
Secondary accession number(s): A4D7U1, Q0PEH2, Q5VYH3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: December 1, 2000
Last modified: May 23, 2018
This is version 152 of the entry and version 1 of the sequence. See 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

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