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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

  • chemorepellent activity Source: Ensembl
  • 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

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.

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

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

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.
GeneTreeiENSGT00860000133877.
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.
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_005269444.4. [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: September 27, 2017
This is version 150 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

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