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P43322 (NRG1_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified May 14, 2014. Version 127. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Pro-neuregulin-1, membrane-bound isoform

Short name=Pro-NRG1

Cleaved into the following chain:

  1. Neuregulin-1
    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 names
Name:Nrg1
Synonyms:Ndf
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length662 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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 vessicles 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 By similarity. Ref.7

Subunit structure

The cytoplasmic domain interacts with the LIM domain region of LIMK1. Interacts with ERBB3 and ERBB4. Ref.5

Subcellular location

Pro-neuregulin-1, membrane-bound isoform: Cell membrane; Single-pass type I membrane protein. Note: Does not seem to be active.

Neuregulin-1: Secreted.

Tissue specificity

Widely expressed. Most tissues contain isoform alpha2Aand isoform alpha2B Isoform Alpha2and isoform beta2are 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.

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.

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

Post-translational modification

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.

Sequence similarities

Belongs to the neuregulin family.

Contains 1 EGF-like domain.

Contains 1 Ig-like C2-type (immunoglobulin-like) domain.

Alternative products

This entry describes 8 isoforms produced by alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist.
Isoform Beta4 (identifier: P43322-1)

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.
Isoform Alpha2A (identifier: P43322-2)

Also known as: NDF38;

The sequence of this isoform differs from the canonical sequence as follows:
     213-256: PNEFTGDRCQNYVMASFYMTSRRKRQETEKPLERKLDHSLVKES → QPGFTGARCTENVPMKVQTQE
Isoform Alpha2B (identifier: P43322-3)

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.
Isoform Alpha2C (identifier: P43322-4)

Also known as: NDF44;

The sequence of this isoform differs from the canonical sequence as follows:
     213-256: PNEFTGDRCQNYVMASFYMTSRRKRQETEKPLERKLDHSLVKES → QPGFTGARCTENVPMKVQTQE
     446-662: Missing.
Isoform Beta1 (identifier: P43322-5)

The sequence of this isoform differs from the canonical sequence as follows:
     231-257: MTSRRKRQETEKPLERKLDHSLVKESK → KHLGIEFME
Isoform Beta2 (identifier: P43322-6)

Also known as: NDF40;

The sequence of this isoform differs from the canonical sequence as follows:
     231-256: Missing.
     325-330: PPENVQ → RVRTRG
Isoform BetA2A (identifier: P43322-7)

Also known as: NDF22;

The sequence of this isoform differs from the canonical sequence as follows:
     231-256: Missing.
Isoform Beta3 (identifier: P43322-8)

Also known as: NDF4;

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Propeptide1 – 1313
PRO_0000019465
Chain14 – 662649Pro-neuregulin-1, membrane-bound isoform
PRO_0000019466
Chain14 – 264251Neuregulin-1
PRO_0000019467

Regions

Topological domain14 – 265252Extracellular Potential
Transmembrane266 – 28823Helical; Note=Internal signal sequence; Potential
Topological domain289 – 662374Cytoplasmic Potential
Domain37 – 12892Ig-like C2-type
Domain178 – 22245EGF-like
Compositional bias165 – 17713Ser/Thr-rich

Amino acid modifications

Glycosylation1201N-linked (GlcNAc...) Potential
Glycosylation1261N-linked (GlcNAc...) Potential
Glycosylation1641N-linked (GlcNAc...) Potential
Disulfide bond57 ↔ 112
Disulfide bond182 ↔ 196 By similarity
Disulfide bond190 ↔ 210 By similarity
Disulfide bond212 ↔ 221 By similarity

Natural variations

Alternative sequence213 – 25644PNEFT…LVKES → QPGFTGARCTENVPMKVQTQ E in isoform Alpha2A, isoform Alpha2B and isoform Alpha2C.
VSP_003436
Alternative sequence231 – 25727MTSRR…VKESK → KHLGIEFME in isoform Beta1.
VSP_003437
Alternative sequence231 – 25626Missing in isoform Beta2 and isoform BetA2A.
VSP_003440
Alternative sequence231 – 24111MTSRRKRQETE → STSTPFLSLPE in isoform Beta3.
VSP_003438
Alternative sequence242 – 662421Missing in isoform Beta3.
VSP_003439
Alternative sequence325 – 3306PPENVQ → RVRTRG in isoform Beta2.
VSP_003441
Alternative sequence446 – 662217Missing in isoform Alpha2C.
VSP_003442
Alternative sequence446 – 48439YVSAM…SMTVS → HNLIAELRRNKAYRSKCMQI QLSATHLRPSSITHLGFIL in isoform Alpha2B.
VSP_003443
Alternative sequence485 – 662178Missing in isoform Alpha2B.
VSP_003444

Experimental info

Sequence conflict901K → N AA sequence Ref.2
Sequence conflict1371T → I AA sequence Ref.2
Sequence conflict2081Y → S AA sequence Ref.2

Sequences

Sequence LengthMass (Da)Tools
Isoform Beta4 (NDF42A) [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 1C31ABCF2A8EB1D5

FASTA66273,288
        10         20         30         40         50         60 
MSERKEGRGK GKGKKKDRGS RGKPGPAEGD PSPALPPRLK EMKSQESAAG SKLVLRCETS 

        70         80         90        100        110        120 
SEYSSLRFKW FKNGNELNRK NKPENIKIQK KPGKSELRIN KASLADSGEY MCKVISKLGN 

       130        140        150        160        170        180 
DSASANITIV ESNEFITGMP ASTETAYVSS ESPIRISVST EGANTSSSTS TSTTGTSHLI 

       190        200        210        220        230        240 
KCAEKEKTFC VNGGECFTVK DLSNPSRYLC KCPNEFTGDR CQNYVMASFY MTSRRKRQET 

       250        260        270        280        290        300 
EKPLERKLDH SLVKESKAEE LYQKRVLTIT GICIALLVVG IMCVVAYCKT KKQRQKLHDR 

       310        320        330        340        350        360 
LRQSLRSERS NLVNIANGPH HPNPPPENVQ LVNQYVSKNV ISSEHIVERE VETSFSTSHY 

       370        380        390        400        410        420 
TSTAHHSTTV TQTPSHSWSN GHTESVISES NSVIMMSSVE NSRHSSPAGG PRGRLHGLGG 

       430        440        450        460        470        480 
PRDNSFLRHA RETPDSYRDS PHSERYVSAM TTPARMSPVD FHTPSSPKSP PSEMSPPVSS 

       490        500        510        520        530        540 
MTVSMPSVAV SPFVEEERPL LLVTPPRLRE KKYDHHPQQL NSFHHNPAHQ STSLPPSPLR 

       550        560        570        580        590        600 
IVEDEEYETT QEYESVQEPV KKVTNSRRAK RTKPNGHIAN RLEMDSNTSS VSSNSESETE 

       610        620        630        640        650        660 
DERVGEDTPF LGIQNPLAAS LEVAPAFRLA ESRTNPAGRF STQEELQARL SSVIANQDPI 


AV 

« Hide

Isoform Alpha2A (NDF38) [UniParc].

Checksum: 2A5A97DFCE065176
Show »

FASTA63970,303
Isoform Alpha2B (NDF19) [UniParc].

Checksum: BE384394D3C88841
Show »

FASTA46150,809
Isoform Alpha2C (NDF44) [UniParc].

Checksum: AD15AECCB42C9C45
Show »

FASTA42246,309
Isoform Beta1 [UniParc].

Checksum: 2382B5DB8682CE17
Show »

FASTA64471,081
Isoform Beta2 (NDF40) [UniParc].

Checksum: 2F621966AA232AB9
Show »

FASTA63670,185
Isoform BetA2A (NDF22) [UniParc].

Checksum: 995A0710F6F48763
Show »

FASTA63670,123
Isoform Beta3 (NDF4) [UniParc].

Checksum: 556F9540DD94B32B
Show »

FASTA24126,213

References

« Hide 'large scale' references
[1]"Structural and functional aspects of the multiplicity of Neu differentiation factors."
Wen D., Suggs S.V., Karunagaran D., Liu N., Cupples R.L., Luo Y., Janssen A.M., Ben-Baruch N., Trollinger D.B., Jacobsen V.L., Meng S.-Y., Lu H.S., Hu S., Chang D., Yang W., Yanigahara D., Koski R.A., Yarden Y.
Mol. Cell. Biol. 14:1909-1919(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], ALTERNATIVE SPLICING.
Tissue: Fibroblast.
[2]"Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit."
Wen D., Peles E., Cupples R., Suggs S.V., Bacus S.S., Luo Y., Trail G., Hu S., Silbiger S.M., Levy R.B., Koski R.A., Lu H.S., Yarden Y.
Cell 69:559-572(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA2C), PARTIAL PROTEIN SEQUENCE.
Tissue: Fibroblast.
[3]"Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells."
Peles E., Bacus S.S., Koski R.A., Lu H.S., Wen D., Ogden S.G., Levy R.B., Yarden Y.
Cell 69:205-216(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 14-36.
[4]"Release of the neuregulin functional polypeptide requires its cytoplasmic tail."
Liu X., Hwang H., Cao L., Wen D., Liu N., Graham R.M., Zhou M.
J. Biol. Chem. 273:34335-34340(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: REGULATION OF PROCESSING (ISOFORM ALPHA2C).
[5]"Transmembrane neuregulins interact with LIM kinase 1, a cytoplasmic protein kinase implicated in development of visuospatial cognition."
Wang J.Y., Frenzel K.E., Wen D., Falls D.L.
J. Biol. Chem. 273:20525-20534(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH LIMK1.
[6]"Quantitative phosphoproteomics of vasopressin-sensitive renal cells: regulation of aquaporin-2 phosphorylation at two sites."
Hoffert J.D., Pisitkun T., Wang G., Shen R.-F., Knepper M.A.
Proc. Natl. Acad. Sci. U.S.A. 103:7159-7164(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[7]"Stimulated ErbB4 internalization is necessary for neuregulin signaling in neurons."
Liu Y., Tao Y.M., Woo R.S., Xiong W.C., Mei L.
Biochem. Biophys. Res. Commun. 354:505-510(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
PIRI61718.
I61719.
I61722.
RefSeqNP_001258052.1. NM_001271123.1. [P43322-8]
UniGeneRn.37438.

3D structure databases

ProteinModelPortalP43322.
SMRP43322. Positions 177-225.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

MINTMINT-4996739.

PTM databases

PhosphoSiteP43322.

Proteomic databases

PaxDbP43322.
PRIDEP43322.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID112400.
KEGGrno:112400.
UCSCRGD:621341. rat. [P43322-1]

Organism-specific databases

CTD3084.
RGD621341. Nrg1.

Phylogenomic databases

eggNOGNOG47801.
HOVERGENHBG006531.
KOK05455.
PhylomeDBP43322.

Gene expression databases

GenevestigatorP43322.

Family and domain databases

Gene3D2.60.40.10. 1 hit.
InterProIPR000742. EG-like_dom.
IPR013032. EGF-like_CS.
IPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR013098. Ig_I-set.
IPR003598. Ig_sub2.
IPR018250. Neuregulin.
IPR002154. Neuregulin_1_C.
[Graphical view]
PfamPF07679. I-set. 1 hit.
PF02158. Neuregulin. 1 hit.
[Graphical view]
PRINTSPR01089. NEUREGULIN.
SMARTSM00181. EGF. 1 hit.
SM00408. IGc2. 1 hit.
[Graphical view]
PROSITEPS00022. EGF_1. 1 hit.
PS50026. EGF_3. 1 hit.
PS50835. IG_LIKE. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio617943.

Entry information

Entry nameNRG1_RAT
AccessionPrimary (citable) accession number: P43322
Secondary accession number(s): P43323 expand/collapse secondary AC list , P43324, P43325, P43326, P43327, P43328
Entry history
Integrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: November 1, 1996
Last modified: May 14, 2014
This is version 127 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families