NEP_RAT
ID NEP_RAT Reviewed; 750 AA.
AC P07861;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 03-AUG-2022, entry version 181.
DE RecName: Full=Neprilysin;
DE EC=3.4.24.11 {ECO:0000269|PubMed:2703483};
DE AltName: Full=Atriopeptidase;
DE AltName: Full=Enkephalinase;
DE AltName: Full=Neutral endopeptidase 24.11;
DE Short=NEP;
DE Short=Neutral endopeptidase;
DE AltName: Full=Skin fibroblast elastase;
DE Short=SFE;
DE AltName: CD_antigen=CD10;
GN Name=Mme;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=3555489; DOI=10.1016/s0006-291x(87)80475-8;
RA Malfroy B., Schofield P.R., Kuang W.-J., Seeburg P.H., Mason A.J.,
RA Henzel W.J.;
RT "Molecular cloning and amino acid sequence of rat enkephalinase.";
RL Biochem. Biophys. Res. Commun. 144:59-66(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP FUNCTION.
RX PubMed=2966343; DOI=10.1016/0196-9781(88)90024-1;
RA Sonnenberg J.L., Sakane Y., Jeng A.Y., Koehn J.A., Ansell J.A.,
RA Wennogle L.P., Ghai R.D.;
RT "Identification of protease 3.4.24.11 as the major atrial natriuretic
RT factor degrading enzyme in the rat kidney.";
RL Peptides 9:173-180(1988).
RN [4]
RP CATALYTIC ACTIVITY, AND SITE ARG-103.
RX PubMed=2703483; DOI=10.1016/s0021-9258(18)83325-7;
RA Bateman R.C. Jr., Jackson D., Slaughter C.A., Unnithan S., Chai Y.G.,
RA Moomaw C., Hersh L.B.;
RT "Identification of the active-site arginine in rat neutral endopeptidase
RT 24.11 (enkephalinase) as arginine 102 and analysis of a glutamine 102
RT mutant.";
RL J. Biol. Chem. 264:6151-6157(1989).
RN [5]
RP INHIBITION BY SIALORPHIN.
RX PubMed=12835417; DOI=10.1073/pnas.1431850100;
RA Rougeot C., Messaoudi M., Hermitte V., Rigault A.G., Blisnick T.,
RA Dugave C., Desor D., Rougeon F.;
RT "Sialorphin, a natural inhibitor of rat membrane-bound neutral
RT endopeptidase that displays analgesic activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:8549-8554(2003).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-6, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Thermolysin-like specificity, but is almost confined on
CC acting on polypeptides of up to 30 amino acids (PubMed:2966343).
CC Biologically important in the destruction of opioid peptides such as
CC Met- and Leu-enkephalins by cleavage of a Gly-Phe bond
CC (PubMed:2966343). Catalyzes cleavage of bradykinin, substance P and
CC neurotensin peptides (By similarity). Able to cleave angiotensin-1,
CC angiotensin-2 and angiotensin 1-9 (PubMed:2966343). Involved in the
CC degradation of the atrial natriuretic factor (ANF) (PubMed:2966343).
CC Displays UV-inducible elastase activity toward skin preelastic and
CC elastic fibers (By similarity). {ECO:0000250|UniProtKB:P08473,
CC ECO:0000269|PubMed:2966343}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Preferential cleavage of polypeptides between hydrophobic
CC residues, particularly with Phe or Tyr at P1'.; EC=3.4.24.11;
CC Evidence={ECO:0000269|PubMed:2703483};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + substance P = L-Leu-L-Met-NH2 + substance P(1-9);
CC Xref=Rhea:RHEA:71459, ChEBI:CHEBI:15377, ChEBI:CHEBI:190692,
CC ChEBI:CHEBI:190693, ChEBI:CHEBI:190700;
CC Evidence={ECO:0000250|UniProtKB:P08473};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:71460;
CC Evidence={ECO:0000250|UniProtKB:P08473};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + substance P = L-Phe-Gly-L-Leu-L-Met-NH2 + substance P(1-
CC 7); Xref=Rhea:RHEA:71467, ChEBI:CHEBI:15377, ChEBI:CHEBI:190692,
CC ChEBI:CHEBI:190695, ChEBI:CHEBI:190698;
CC Evidence={ECO:0000250|UniProtKB:P08473};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:71468;
CC Evidence={ECO:0000250|UniProtKB:P08473};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + neurotensin = L-isoleucyl-L-leucine + neurotensin(1-11);
CC Xref=Rhea:RHEA:71475, ChEBI:CHEBI:15377, ChEBI:CHEBI:147362,
CC ChEBI:CHEBI:190704, ChEBI:CHEBI:190706;
CC Evidence={ECO:0000250|UniProtKB:P08473};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:71476;
CC Evidence={ECO:0000250|UniProtKB:P08473};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + neurotensin = L-tyrosyl-L-isoleucyl-L-leucine +
CC neurotensin(1-10); Xref=Rhea:RHEA:71479, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:147362, ChEBI:CHEBI:190705, ChEBI:CHEBI:190707;
CC Evidence={ECO:0000250|UniProtKB:P08473};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:71480;
CC Evidence={ECO:0000250|UniProtKB:P08473};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P08473};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:P08473};
CC -!- ACTIVITY REGULATION: Inhibited in a dose dependent manner by
CC sialorphin. {ECO:0000269|PubMed:12835417}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P08473};
CC Single-pass type II membrane protein {ECO:0000255}.
CC -!- PTM: Myristoylation is a determinant of membrane targeting.
CC {ECO:0000250|UniProtKB:P08473}.
CC -!- PTM: Glycosylation at Asn-628 is necessary both for surface expression
CC and neutral endopeptidase activity. {ECO:0000250|UniProtKB:P08473}.
CC -!- SIMILARITY: Belongs to the peptidase M13 family. {ECO:0000255|PROSITE-
CC ProRule:PRU01233, ECO:0000305}.
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DR EMBL; M15944; AAA41116.1; -; mRNA.
DR EMBL; BC085753; AAH85753.1; -; mRNA.
DR PIR; A29295; HYRTN.
DR RefSeq; NP_036740.1; NM_012608.2.
DR RefSeq; XP_006232499.1; XM_006232437.3.
DR RefSeq; XP_017446118.1; XM_017590629.1.
DR RefSeq; XP_017446119.1; XM_017590630.1.
DR AlphaFoldDB; P07861; -.
DR SMR; P07861; -.
DR STRING; 10116.ENSRNOP00000044578; -.
DR BindingDB; P07861; -.
DR ChEMBL; CHEMBL3369; -.
DR DrugCentral; P07861; -.
DR GuidetoPHARMACOLOGY; 1611; -.
DR MEROPS; M13.001; -.
DR GlyGen; P07861; 6 sites.
DR iPTMnet; P07861; -.
DR PhosphoSitePlus; P07861; -.
DR PaxDb; P07861; -.
DR PRIDE; P07861; -.
DR Ensembl; ENSRNOT00000042576; ENSRNOP00000044578; ENSRNOG00000009514.
DR GeneID; 24590; -.
DR KEGG; rno:24590; -.
DR UCSC; RGD:3098; rat.
DR CTD; 4311; -.
DR RGD; 3098; Mme.
DR eggNOG; KOG3624; Eukaryota.
DR GeneTree; ENSGT00940000156745; -.
DR HOGENOM; CLU_006187_4_1_1; -.
DR InParanoid; P07861; -.
DR OMA; GYPDEIM; -.
DR OrthoDB; 282463at2759; -.
DR PhylomeDB; P07861; -.
DR TreeFam; TF315192; -.
DR BRENDA; 3.4.24.11; 5301.
DR Reactome; R-RNO-2022377; Metabolism of Angiotensinogen to Angiotensins.
DR Reactome; R-RNO-6798695; Neutrophil degranulation.
DR PRO; PR:P07861; -.
DR Proteomes; UP000002494; Chromosome 2.
DR Bgee; ENSRNOG00000009514; Expressed in jejunum and 20 other tissues.
DR ExpressionAtlas; P07861; baseline and differential.
DR Genevisible; P07861; RN.
DR GO; GO:0030424; C:axon; ISS:UniProtKB.
DR GO; GO:0005903; C:brush border; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; ISO:RGD.
DR GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR GO; GO:0005769; C:early endosome; ISO:RGD.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; IDA:RGD.
DR GO; GO:0045121; C:membrane raft; ISO:RGD.
DR GO; GO:0044306; C:neuron projection terminus; ISS:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0098793; C:presynapse; ISO:RGD.
DR GO; GO:0045202; C:synapse; ISS:UniProtKB.
DR GO; GO:0008021; C:synaptic vesicle; ISS:UniProtKB.
DR GO; GO:0005802; C:trans-Golgi network; ISO:RGD.
DR GO; GO:1901612; F:cardiolipin binding; ISO:RGD.
DR GO; GO:0004175; F:endopeptidase activity; ISO:RGD.
DR GO; GO:0008238; F:exopeptidase activity; ISO:RGD.
DR GO; GO:0004222; F:metalloendopeptidase activity; ISS:UniProtKB.
DR GO; GO:0070012; F:oligopeptidase activity; IDA:RGD.
DR GO; GO:0008233; F:peptidase activity; ISO:RGD.
DR GO; GO:0042277; F:peptide binding; IDA:RGD.
DR GO; GO:0001786; F:phosphatidylserine binding; ISO:RGD.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0007568; P:aging; ISO:RGD.
DR GO; GO:0097242; P:amyloid-beta clearance; IDA:ARUK-UCL.
DR GO; GO:0150094; P:amyloid-beta clearance by cellular catabolic process; IMP:ARUK-UCL.
DR GO; GO:0050435; P:amyloid-beta metabolic process; ISS:UniProtKB.
DR GO; GO:0010815; P:bradykinin catabolic process; ISS:UniProtKB.
DR GO; GO:0071345; P:cellular response to cytokine stimulus; ISS:UniProtKB.
DR GO; GO:0071492; P:cellular response to UV-A; ISS:UniProtKB.
DR GO; GO:0071493; P:cellular response to UV-B; ISS:UniProtKB.
DR GO; GO:0046449; P:creatinine metabolic process; ISS:UniProtKB.
DR GO; GO:0042447; P:hormone catabolic process; ISS:UniProtKB.
DR GO; GO:0001822; P:kidney development; IEP:RGD.
DR GO; GO:0007611; P:learning or memory; ISO:RGD.
DR GO; GO:0030324; P:lung development; IEP:RGD.
DR GO; GO:0061837; P:neuropeptide processing; ISO:RGD.
DR GO; GO:0006518; P:peptide metabolic process; IMP:RGD.
DR GO; GO:0001890; P:placenta development; IEP:RGD.
DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISO:RGD.
DR GO; GO:0050769; P:positive regulation of neurogenesis; ISO:RGD.
DR GO; GO:0030163; P:protein catabolic process; IDA:RGD.
DR GO; GO:0016485; P:protein processing; IBA:GO_Central.
DR GO; GO:0006508; P:proteolysis; ISO:RGD.
DR GO; GO:0090399; P:replicative senescence; ISS:UniProtKB.
DR GO; GO:0043627; P:response to estrogen; IDA:RGD.
DR GO; GO:0019233; P:sensory perception of pain; ISS:UniProtKB.
DR GO; GO:0010814; P:substance P catabolic process; ISS:UniProtKB.
DR CDD; cd08662; M13; 1.
DR Gene3D; 1.10.1380.10; -; 1.
DR Gene3D; 3.40.390.10; -; 1.
DR InterPro; IPR024079; MetalloPept_cat_dom_sf.
DR InterPro; IPR029727; MME/CD10/NEP.
DR InterPro; IPR000718; Peptidase_M13.
DR InterPro; IPR018497; Peptidase_M13_C.
DR InterPro; IPR042089; Peptidase_M13_dom_2.
DR InterPro; IPR008753; Peptidase_M13_N.
DR PANTHER; PTHR11733; PTHR11733; 1.
DR PANTHER; PTHR11733:SF114; PTHR11733:SF114; 1.
DR Pfam; PF01431; Peptidase_M13; 1.
DR Pfam; PF05649; Peptidase_M13_N; 1.
DR PRINTS; PR00786; NEPRILYSIN.
DR PROSITE; PS51885; NEPRILYSIN; 1.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Hydrolase; Lipoprotein; Membrane; Metal-binding; Metalloprotease;
KW Myristate; Phosphoprotein; Protease; Reference proteome; Signal-anchor;
KW Transmembrane; Transmembrane helix; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT CHAIN 2..750
FT /note="Neprilysin"
FT /id="PRO_0000078217"
FT TOPO_DOM 2..28
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 29..51
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 52..750
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT DOMAIN 56..750
FT /note="Peptidase M13"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT MOTIF 16..23
FT /note="Stop-transfer sequence"
FT /evidence="ECO:0000255"
FT ACT_SITE 585
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT ACT_SITE 651
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT BINDING 103
FT /ligand="a peptide"
FT /ligand_id="ChEBI:CHEBI:60466"
FT /ligand_note="substrate"
FT /evidence="ECO:0000269|PubMed:2703483"
FT BINDING 584
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 588
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 647
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT MOD_RES 4
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P08473"
FT MOD_RES 6
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT LIPID 2
FT /note="N-myristoyl glycine"
FT /evidence="ECO:0000250|UniProtKB:P08473"
FT CARBOHYD 145
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250|UniProtKB:P08473"
FT CARBOHYD 211
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 285
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 311
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:3555489"
FT CARBOHYD 325
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250|UniProtKB:P08473"
FT CARBOHYD 628
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250|UniProtKB:P08473"
FT DISULFID 57..62
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 80..735
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 88..695
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 143..411
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 234..242
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 621..747
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
SQ SEQUENCE 750 AA; 85795 MW; 609D4716C4B15CBC CRC64;
MGRSESQMDI TDINAPKPKK KQRWTPLEIS LSVLVLLLTI IAVTMIALYA TYDDGICKSS
DCIKSAARLI QNMDASAEPC TDFFKYACGG WLKRNVIPET SSRYSNFDIL RDELEVILKD
VLQEPKTEDI VAVQKAKTLY RSCINESAID SRGGQPLLTL LPDIYGWPVA SQNWEQTYGT
SWTAEKSIAQ LNSKYGKKVL INFFVGTDDK NSTQHIIHFD QPRLGLPSRD YYECTGIYKE
ACTAYVDFMI SVARLIRQEQ RLPIDENQLS LEMNKVMELE KEIANATTKP EDRNDPMLLY
NKMTLAKLQN NFSLEINGKP FSWSNFTNEI MSTVNINIQN EEEVVVYAPE YLTKLKPILT
KYSPRDLQNL MSWRFIMDLV SSLSRNYKES RNAFRKALYG TTSETATWRR CANYVNGNME
NAVGRLYVEA AFAGESKHVV EDLIAQIREV FIQTLDDLTW MDAETKKKAE EKALAIKERI
GYPDDIISNE NKLNNEYLEL NYKEEEYFEN IIQNLKFSQS KQLKKLREKV DKDEWISGAA
VVNAFYSSGR NQIVFPAGIL QPPFFSARQS NSLNYGGIGM VIGHEITHGF DDNGRNFNKD
GDLVDWWTQQ SANNFKDQSQ CMVYQYGNFT WDLAGGQHLN GINTLGENIA DNGGIGQAYR
AYQNYVKKNG EEKLLPGLDL NHKQLFFLNF AQVWCGTYRP EYAVNSIKTD VHSPGNFRII
GTLQNSAEFA DAFHCRKNSY MNPERKCRVW
