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Protein

Pro-neuregulin-1, membrane-bound isoform

Gene

Nrg1

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors. Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors. The multiple isoforms perform diverse functions such as inducing growth and differentiation of epithelial, glial, neuronal, and skeletal muscle cells; inducing expression of acetylcholine receptor in synaptic vesicles during the formation of the neuromuscular junction; stimulating lobuloalveolar budding and milk production in the mammary gland and inducing differentiation of mammary tumor cells; stimulating Schwann cell proliferation; implication in the development of the myocardium such as trabeculation of the developing heart. Binds to ERBB4 and ERBB3. Acts as a ligand for integrins and binds (via EGF domain) to integrins ITGAV:ITGB3 or ITGA6:ITGB4. Its binding to integrins and subsequent ternary complex formation with integrins and ERRB3 are essential for NRG1-ERBB signaling (By similarity). Induces the phosphorylation and activation of MAPK3/ERK1, MAPK1/ERK2 and AKT1, and ligand-dependent ERBB4 endocytosis is essential for the NRG1-mediated activation of these kinases in neurons (PubMed:17250808).By similarity1 Publication

GO - Molecular functioni

GO - Biological processi

  • activation of MAPK activity Source: UniProtKB
  • activation of protein kinase B activity Source: UniProtKB
  • animal organ development Source: GO_Central
  • embryo development Source: InterPro
  • ERBB signaling pathway Source: UniProtKB
  • intracellular signal transduction Source: GO_Central
  • memory Source: RGD
  • negative regulation of corticosterone secretion Source: RGD
  • positive regulation of axon regeneration Source: RGD
  • positive regulation of cell proliferation Source: RGD
  • positive regulation of neuron projection development Source: RGD
  • positive regulation of peptidyl-tyrosine phosphorylation Source: RGD
  • positive regulation of Schwann cell proliferation Source: RGD
  • response to progesterone Source: RGD

Keywordsi

Molecular functionGrowth factor

Names & Taxonomyi

Protein namesi
Recommended name:
Pro-neuregulin-1, membrane-bound isoform
Short name:
Pro-NRG1
Cleaved into the following chain:
Alternative name(s):
Acetylcholine receptor-inducing activity
Short name:
ARIA
Glial growth factor
Heregulin
Short name:
HRG
Neu differentiation factor
Sensory and motor neuron-derived factor
Gene namesi
Name:Nrg1
Synonyms:Ndf
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi621341 Nrg1

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 domaini14 – 265ExtracellularSequence analysisAdd BLAST252
Transmembranei266 – 288Helical; Note=Internal signal sequenceSequence analysisAdd BLAST23
Topological domaini289 – 662CytoplasmicSequence analysisAdd BLAST374

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
PropeptideiPRO_00000194651 – 131 PublicationAdd BLAST13
ChainiPRO_000001946614 – 662Pro-neuregulin-1, membrane-bound isoformAdd BLAST649
ChainiPRO_000001946714 – 264Neuregulin-1Add BLAST251

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi57 ↔ 112
Glycosylationi120N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi126N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi164N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi182 ↔ 196By similarity
Disulfide bondi190 ↔ 210By similarity
Disulfide bondi212 ↔ 221By similarity

Post-translational modificationi

Proteolytic cleavage close to the plasma membrane on the external face leads to the release of the soluble growth factor form.
N- and O-glycosylated (By similarity). Extensive glycosylation precedes the proteolytic cleavage.By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiP43322
PRIDEiP43322

PTM databases

iPTMnetiP43322
PhosphoSitePlusiP43322

Expressioni

Tissue specificityi

Widely expressed. Most tissues contain isoform alpha2A and isoform alpha2B. Isoform Alpha2 and isoform beta2 are the predominant forms in mesenchymal and non-neuronal organs. Isoform Beta1 is enriched in brain and spinal cord, but not in muscle and heart. Isoform Alpha2C is highly expressed in spinal cord, moderately in lung, brain, ovary, and stomach, in low amounts in the kidney, skin and heart and not detected in the liver, spleen, and placenta.

Interactioni

Subunit structurei

The cytoplasmic domain interacts with the LIM domain region of LIMK1 (PubMed:9685409). Forms a ternary complex with ERBB3 and ITGAV:ITGB3 or ITGA6:ITGB4 (By similarity).By similarity1 Publication

GO - Molecular functioni

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000014268

Structurei

3D structure databases

ProteinModelPortaliP43322
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini37 – 128Ig-like C2-typeAdd BLAST92
Domaini178 – 222EGF-likePROSITE-ProRule annotationAdd BLAST45

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi165 – 177Ser/Thr-richAdd BLAST13

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

Sequence similaritiesi

Belongs to the neuregulin family.Curated

Keywords - Domaini

EGF-like domain, Immunoglobulin domain, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IEU9 Eukaryota
ENOG4110ST7 LUCA
HOVERGENiHBG006531
InParanoidiP43322
KOiK05455
PhylomeDBiP43322

Family and domain databases

Gene3Di2.60.40.10, 1 hit
InterProiView protein in InterPro
IPR013032 EGF-like_CS
IPR000742 EGF-like_dom
IPR007110 Ig-like_dom
IPR036179 Ig-like_dom_sf
IPR013783 Ig-like_fold
IPR013098 Ig_I-set
IPR003599 Ig_sub
IPR003598 Ig_sub2
IPR002154 Neuregulin_C
IPR018250 NRG1
PANTHERiPTHR11100:SF7 PTHR11100:SF7, 1 hit
PfamiView protein in Pfam
PF07679 I-set, 1 hit
PF02158 Neuregulin, 1 hit
PRINTSiPR01089 NEUREGULIN
SMARTiView protein in SMART
SM00181 EGF, 1 hit
SM00409 IG, 1 hit
SM00408 IGc2, 1 hit
SUPFAMiSSF48726 SSF48726, 1 hit
PROSITEiView protein in PROSITE
PS00022 EGF_1, 1 hit
PS50026 EGF_3, 1 hit
PS50835 IG_LIKE, 1 hit

Sequences (8)i

Sequence statusi: Complete.

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

This entry describes 8 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Additional isoforms seem to exist.
Isoform Beta4 (identifier: P43322-1) [UniParc]FASTAAdd to basket
Also known as: NDF42A

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
MSERKEGRGK GKGKKKDRGS RGKPGPAEGD PSPALPPRLK EMKSQESAAG
60 70 80 90 100
SKLVLRCETS SEYSSLRFKW FKNGNELNRK NKPENIKIQK KPGKSELRIN
110 120 130 140 150
KASLADSGEY MCKVISKLGN DSASANITIV ESNEFITGMP ASTETAYVSS
160 170 180 190 200
ESPIRISVST EGANTSSSTS TSTTGTSHLI KCAEKEKTFC VNGGECFTVK
210 220 230 240 250
DLSNPSRYLC KCPNEFTGDR CQNYVMASFY MTSRRKRQET EKPLERKLDH
260 270 280 290 300
SLVKESKAEE LYQKRVLTIT GICIALLVVG IMCVVAYCKT KKQRQKLHDR
310 320 330 340 350
LRQSLRSERS NLVNIANGPH HPNPPPENVQ LVNQYVSKNV ISSEHIVERE
360 370 380 390 400
VETSFSTSHY TSTAHHSTTV TQTPSHSWSN GHTESVISES NSVIMMSSVE
410 420 430 440 450
NSRHSSPAGG PRGRLHGLGG PRDNSFLRHA RETPDSYRDS PHSERYVSAM
460 470 480 490 500
TTPARMSPVD FHTPSSPKSP PSEMSPPVSS MTVSMPSVAV SPFVEEERPL
510 520 530 540 550
LLVTPPRLRE KKYDHHPQQL NSFHHNPAHQ STSLPPSPLR IVEDEEYETT
560 570 580 590 600
QEYESVQEPV KKVTNSRRAK RTKPNGHIAN RLEMDSNTSS VSSNSESETE
610 620 630 640 650
DERVGEDTPF LGIQNPLAAS LEVAPAFRLA ESRTNPAGRF STQEELQARL
660
SSVIANQDPI AV
Length:662
Mass (Da):73,288
Last modified:November 1, 1996 - v1
Checksum:i1C31ABCF2A8EB1D5
GO
Isoform Alpha2A (identifier: P43322-2) [UniParc]FASTAAdd to basket
Also known as: NDF38

The sequence of this isoform differs from the canonical sequence as follows:
     213-256: PNEFTGDRCQNYVMASFYMTSRRKRQETEKPLERKLDHSLVKES → QPGFTGARCTENVPMKVQTQE

Show »
Length:639
Mass (Da):70,303
Checksum:i2A5A97DFCE065176
GO
Isoform Alpha2B (identifier: P43322-3) [UniParc]FASTAAdd to basket
Also known as: NDF19

The sequence of this isoform differs from the canonical sequence as follows:
     213-256: PNEFTGDRCQNYVMASFYMTSRRKRQETEKPLERKLDHSLVKES → QPGFTGARCTENVPMKVQTQE
     446-484: YVSAMTTPAR...SPPVSSMTVS → HNLIAELRRN...SSITHLGFIL
     485-662: Missing.

Show »
Length:461
Mass (Da):50,809
Checksum:iBE384394D3C88841
GO
Isoform Alpha2C (identifier: P43322-4) [UniParc]FASTAAdd to basket
Also known as: NDF44

The sequence of this isoform differs from the canonical sequence as follows:
     213-256: PNEFTGDRCQNYVMASFYMTSRRKRQETEKPLERKLDHSLVKES → QPGFTGARCTENVPMKVQTQE
     446-662: Missing.

Show »
Length:422
Mass (Da):46,309
Checksum:iAD15AECCB42C9C45
GO
Isoform Beta1 (identifier: P43322-5) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     231-257: MTSRRKRQETEKPLERKLDHSLVKESK → KHLGIEFME

Show »
Length:644
Mass (Da):71,081
Checksum:i2382B5DB8682CE17
GO
Isoform Beta2 (identifier: P43322-6) [UniParc]FASTAAdd to basket
Also known as: NDF40

The sequence of this isoform differs from the canonical sequence as follows:
     231-256: Missing.
     325-330: PPENVQ → RVRTRG

Show »
Length:636
Mass (Da):70,185
Checksum:i2F621966AA232AB9
GO
Isoform BetA2A (identifier: P43322-7) [UniParc]FASTAAdd to basket
Also known as: NDF22

The sequence of this isoform differs from the canonical sequence as follows:
     231-256: Missing.

Show »
Length:636
Mass (Da):70,123
Checksum:i995A0710F6F48763
GO
Isoform Beta3 (identifier: P43322-8) [UniParc]FASTAAdd to basket
Also known as: NDF4

The sequence of this isoform differs from the canonical sequence as follows:
     231-241: MTSRRKRQETE → STSTPFLSLPE
     242-662: Missing.

Show »
Length:241
Mass (Da):26,213
Checksum:i556F9540DD94B32B
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti90K → N AA sequence (PubMed:1349853).Curated1
Sequence conflicti137T → I AA sequence (PubMed:1349853).Curated1
Sequence conflicti208Y → S AA sequence (PubMed:1349853).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_003436213 – 256PNEFT…LVKES → QPGFTGARCTENVPMKVQTQ E in isoform Alpha2A, isoform Alpha2B and isoform Alpha2C. 1 PublicationAdd BLAST44
Alternative sequenceiVSP_003437231 – 257MTSRR…VKESK → KHLGIEFME in isoform Beta1. CuratedAdd BLAST27
Alternative sequenceiVSP_003440231 – 256Missing in isoform Beta2 and isoform BetA2A. CuratedAdd BLAST26
Alternative sequenceiVSP_003438231 – 241MTSRRKRQETE → STSTPFLSLPE in isoform Beta3. CuratedAdd BLAST11
Alternative sequenceiVSP_003439242 – 662Missing in isoform Beta3. CuratedAdd BLAST421
Alternative sequenceiVSP_003441325 – 330PPENVQ → RVRTRG in isoform Beta2. Curated6
Alternative sequenceiVSP_003442446 – 662Missing in isoform Alpha2C. 1 PublicationAdd BLAST217
Alternative sequenceiVSP_003443446 – 484YVSAM…SMTVS → HNLIAELRRNKAYRSKCMQI QLSATHLRPSSITHLGFIL in isoform Alpha2B. CuratedAdd BLAST39
Alternative sequenceiVSP_003444485 – 662Missing in isoform Alpha2B. CuratedAdd BLAST178

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U02315 mRNA Translation: AAA19940.1
U02316 mRNA Translation: AAA19941.1
U02317 mRNA Translation: AAA19942.1
U02318 mRNA Translation: AAA19943.1
U02319 mRNA Translation: AAA19944.1
U02320 mRNA Translation: AAA19945.1
U02321 mRNA Translation: AAA19946.1
U02322 mRNA Translation: AAA19947.1
U02323 mRNA Translation: AAA19948.1
U02324 mRNA Translation: AAA19949.1
M92430 mRNA No translation available.
PIRiI61718
I61719
I61722
RefSeqiNP_001258052.1, NM_001271123.1 [P43322-8]
UniGeneiRn.37438

Genome annotation databases

GeneIDi112400
KEGGirno:112400
UCSCiRGD:621341 rat [P43322-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiNRG1_RAT
AccessioniPrimary (citable) accession number: P43322
Secondary accession number(s): P43323
, P43324, P43325, P43326, P43327, P43328
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: November 1, 1996
Last modified: May 23, 2018
This is version 157 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

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