NRG1_HUMAN » Pro-neuregulin-1, membrane-bound isoform

NRG1_HUMAN » Pro-neuregulin-1, membrane-bound isoform
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
NRG1_HUMAN » Pro-neuregulin-1, membrane-bound isoform » Pro-NRG1;
Hydrophobic Thickness 34.4 ± 2.2 Å
Tilt Angle 3 ± 2°
ΔGtransfer -23.8 kcal/mol
ΔGfold -19.9 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, Reactome
Topology Out
TM Segments 243-266 (235-271)
Pathways

ErbB signaling pathway (KEGG)

Immune System (Reactome)

Signal Transduction (Reactome)

PDB 1hre (175-241), 1hrf (175-241), 1hae (177-239), 1haf (177-239), 3u7u (G/H...=175-212)
OPM none
Complexes

NRG1:ERBB4_HUMAN

Interactions

ADA19, Complex: ADA19:NRG1, PubMed

EGFR, Complex: EGFR:NRG1, PubMed

EGF, Complex: EGF:NRG1, PubMed

ERBB2, Complex: NRG1:ERBB2, PubMed

ERBB3, Complex: ERBB3:NRG1, PubMed

ERBB4, Complex: NRG1:ERBB4, PubMed

Domains

AA: 37-129, PDBID: 1CS6, Subunit A, Seq Identity:32%, Immunoglobulin I-set domain

AA: 182-220, PDBID: 1HAE, Subunit A, Seq Identity:100%, EGF-like domain

AA: 235-628, PDBID: 1HAE, Subunit A, Seq Identity:100%, Neuregulin family

UniProt annotation for NRG1_HUMAN » Pro-neuregulin-1, membrane-bound isoform
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 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. Isoform 10 may play a role in motor and sensory neuron development.

SUBUNIT: The cytoplasmic domain interacts with the LIM domain region of LIMK1 (By similarity). Interacts with ERBB3 and ERBB4.

TISSUE SPECIFICITY: Type I isoforms are the predominant forms expressed in the endocardium. Isoform alpha is expressed in breast, ovary, testis, prostate, heart, skeletal muscle, lung, placenta liver, kidney, salivary gland, small intestine and brain, but not in uterus, stomach, pancreas, and spleen. Isoform 3 is the predominant form in mesenchymal cells and in non-neuronal organs, whereas isoform 6 is the major neuronal form. Isoform 8 is expressed in spinal cord and brain. Isoform 9 is the major form in skeletal muscle cells; in the nervous system it is expressed in spinal cord and brain. Also detected in adult heart, placenta, lung, liver, kidney, and pancreas. Isoform 10 is expressed in nervous system: spinal cord motor neurons, dorsal root ganglion neurons, and brain. Predominant isoform expressed in sensory and motor neurons. Not detected in adult heart, placenta, lung, liver, skeletal muscle, kidney, and pancreas. Not expressed in fetal lung, liver and kidney. Type IV isoforms are brain-specific.

DEVELOPMENTAL STAGE: Detectable at early embryonic ages. Isoform 10 is highly expressed in developing spinal motor neurons and in developing cranial nerve nuclei. Expression is maintained only in both adult motor neurons and dorsal root ganglion neurons. Type IV isoforms are expressed in fetal brain.

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 (By similarity).

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

DISEASE: Note=A chromosomal aberration involving NRG1 produces gamma-heregulin. Translocation t(8;11) with TENM4. The translocation fuses the 5"-end of TENM4 to NRG1 (isoform 8). The product of this translocation was first thought to be an alternatively spliced isoform. Gamma-heregulin is a soluble activating ligand for the ERBB2-ERBB3 receptor complex and acts as an autocrine growth factor in a specific breast cancer cell line (MDA-MB-175). Not detected in breast carcinoma samples, including ductal, lobular, medullary, and mucinous histological types, neither in other breast cancer cell lines.

UniProt features for NRG1_HUMAN » Pro-neuregulin-1, membrane-bound isoform
PROPEP 2 19
CHAIN 20 640 Pro-neuregulin-1, membrane-bound isoform.
CHAIN 20 241 Neuregulin-1.
DOMAIN 37 128 Ig-like C2-type.
DOMAIN 178 222 EGF-like.
SITE 34 34 Breakpoint for translocation to form gamma-heregulin.
DISULFID 57 112 By similarity.
DISULFID 182 196
DISULFID 190 210
DISULFID 212 221
Amino Acid Sequence for NRG1_HUMAN » Pro-neuregulin-1, membrane-bound isoform
MSERKEGRGK GKGKKKERGS GKKPESAAGS QSPALPPRLK EMKSQESAAG SKLVLRCETS SEYSSLRFKW FKNGNELNRK NKPQNIKIQK KPGKSELRIN KASLADSGEY MCKVISKLGN DSASANITIV ESNEIITGMP ASTEGAYVSS ESPIRISVST EGANTSSSTS TSTTGTSHLV KCAEKEKTFC VNGGECFMVK DLSNPSRYLC KCQPGFTGAR CTENVPMKVQ NQEKAEELYQ KRVLTITGIC IALLVVGIMC VVAYCKTKKQ RKKLHDRLRQ SLRSERNNMM NIANGPHHPN PPPENVQLVN QYVSKNVISS EHIVEREAET SFSTSHYTST AHHSTTVTQT PSHSWSNGHT ESILSESHSV IVMSSVENSR HSSPTGGPRG RLNGTGGPRE CNSFLRHARE TPDSYRDSPH SERYVSAMTT PARMSPVDFH TPSSPKSPPS EMSPPVSSMT VSMPSMAVSP FMEEERPLLL VTPPRLREKK FDHHPQQFSS FHHNPAHDSN SLPASPLRIV EDEEYETTQE YEPAQEPVKK LANSRRAKRT KPNGHIANRL EVDSNTSSQS SNSESETEDE RVGEDTPFLG IQNPLAASLE ATPAFRLADS RTNPAGRFST QEEIQARLSS VIANQDPIAV