NEP_PONAB
ID NEP_PONAB Reviewed; 750 AA.
AC Q5RE69; Q5R5K3; Q5RFQ2;
DT 26-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 26-FEB-2008, sequence version 2.
DT 03-AUG-2022, entry version 103.
DE RecName: Full=Neprilysin;
DE EC=3.4.24.11 {ECO:0000250|UniProtKB:P08473};
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 Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Thermolysin-like specificity, but is almost confined on
CC acting on polypeptides of up to 30 amino acids. Biologically important
CC in the destruction of opioid peptides such as Met- and Leu-enkephalins
CC by cleavage of a Gly-Phe bond. Catalyzes cleavage of bradykinin,
CC substance P and neurotensin peptides. Able to cleave angiotensin-1,
CC angiotensin-2 and angiotensin 1-9. Involved in the degradation of
CC atrial natriuretic factor (ANF) and brain natriuretic factor (BNP(1-
CC 32)). Displays UV-inducible elastase activity toward skin preelastic
CC and elastic fibers. {ECO:0000250|UniProtKB:P08473}.
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:0000250|UniProtKB:P08473};
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 -!- 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; CR857100; CAH89405.1; -; mRNA.
DR EMBL; CR857668; CAH89938.1; -; mRNA.
DR EMBL; CR860855; CAH92963.1; -; mRNA.
DR RefSeq; NP_001126748.1; NM_001133276.1.
DR AlphaFoldDB; Q5RE69; -.
DR SMR; Q5RE69; -.
DR STRING; 9601.ENSPPYP00000015904; -.
DR MEROPS; M13.001; -.
DR Ensembl; ENSPPYT00000050259; ENSPPYP00000036919; ENSPPYG00000014224.
DR GeneID; 100173750; -.
DR KEGG; pon:100173750; -.
DR CTD; 4311; -.
DR eggNOG; KOG3624; Eukaryota.
DR GeneTree; ENSGT00940000156745; -.
DR HOGENOM; CLU_006187_8_0_1; -.
DR InParanoid; Q5RE69; -.
DR OMA; GYPDEIM; -.
DR OrthoDB; 282463at2759; -.
DR TreeFam; TF315192; -.
DR Proteomes; UP000001595; Chromosome 3.
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:0030425; C:dendrite; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0044306; C:neuron projection terminus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0045202; C:synapse; ISS:UniProtKB.
DR GO; GO:0008021; C:synaptic vesicle; ISS:UniProtKB.
DR GO; GO:0004222; F:metalloendopeptidase activity; ISS:UniProtKB.
DR GO; GO:0042277; F:peptide binding; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
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; ISS:UniProtKB.
DR GO; GO:0006518; P:peptide metabolic process; ISS:UniProtKB.
DR GO; GO:0006508; P:proteolysis; ISS:UniProtKB.
DR GO; GO:0090399; P:replicative senescence; ISS:UniProtKB.
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 2: Evidence at transcript level;
KW Cell membrane; Disulfide bond; Glycoprotein; Hydrolase; Lipoprotein;
KW Membrane; Metal-binding; Metalloprotease; Myristate; Phosphoprotein;
KW Protease; Reference proteome; Signal-anchor; Transmembrane;
KW Transmembrane helix; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P08473"
FT CHAIN 2..750
FT /note="Neprilysin"
FT /id="PRO_0000319885"
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 REGION 1..20
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
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:0000250|UniProtKB:P07861"
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:0000250|UniProtKB:P08473"
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 285
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 311
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 325
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250|UniProtKB:P08473"
FT CARBOHYD 335
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
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"
FT CONFLICT 115
FT /note="E -> G (in Ref. 1; CAH89405)"
FT /evidence="ECO:0000305"
FT CONFLICT 175
FT /note="E -> K (in Ref. 1; CAH89405)"
FT /evidence="ECO:0000305"
FT CONFLICT 523
FT /note="L -> P (in Ref. 1; CAH89938)"
FT /evidence="ECO:0000305"
FT CONFLICT 681
FT /note="N -> S (in Ref. 1; CAH92963)"
FT /evidence="ECO:0000305"
FT CONFLICT 729
FT /note="F -> C (in Ref. 1; CAH92963)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 750 AA; 85514 MW; C4D1216E8361352F CRC64;
MGKSESQMDI TDINTPKPKK KQRWTPLEIS LSVLVLLLTI IAVTMIALYA TYDDGICKSS
DCIKSAARLI QNMDATAEPC TDFFKYACGG WLKRNVIPET SSRYGNFDIL RDELEVVLKD
VLQEPKTEDI VAVQKAKTLY RSCINESAID SRGGEPLLKL LPDVYGWPVA TENWEQKYGA
SWTAEKAIAQ LNSKYGKKVL INLFVGTDDK NSVNHVIHID QPRLGLPSRD YYECTGIYKE
ACTAYVDFMI SVARLIRQEE RLPIDENQLA LEMNKVMELE KEIANATAKP EDRNDPMLLY
KKMTLAQIQN NFSLEINGKP FSWLNFTNEI MSTVNISITN EEDVVVYAPE YLTKLKPILT
KYSARDLQNL MSWRFIMDLV SSLSRTYKES RNAFRKALYG TTSETATWRR CANYVNGNME
NAVGRLYVEA AFAGESKHVV EDLIAQIREV FIQTLDDLTW MDAETKKRAE EKALAIKERI
GYPDDIVSND NKLNNEYLEL NYKEDEYFEN IIQNLKFSQS KQLKKLREKV DKDEWISGAA
VVNAFYSSGR NQIVFPAGIL QPPFFSAQQS NSLNYGGIGM VIGHEITHGF DDNGRNFNKD
GDLVDWWTQQ SASNFKEQSQ CMVYQYGNFS WDLAGGQHLN GINTLGENIA DNGGLGQAYR
AYQNYIKKNG EEKLLPGLDL NHKQLFFLNF AQVWCGTYRP EYAVNSIKTD VHSPGNFRII
GTLQNSAEFS EAFHCRKNSY MNPEKKCRVW
