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 27-MAR-2024, entry version 109. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 GlyCosmos; Q5RE69; 6 sites, No reported glycans. DR Ensembl; ENSPPYT00000050259.1; ENSPPYP00000036919.1; ENSPPYG00000014224.3. 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; YECTGVY; -. DR OrthoDB; 202716at2759; -. 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:0005769; C:early endosome; IEA:Ensembl. DR GO; GO:0045121; C:membrane raft; IEA:Ensembl. DR GO; GO:0044306; C:neuron projection terminus; ISS:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. 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:0005802; C:trans-Golgi network; IEA:Ensembl. DR GO; GO:1901612; F:cardiolipin binding; IEA:Ensembl. DR GO; GO:0008238; F:exopeptidase activity; IEA:Ensembl. DR GO; GO:0004222; F:metalloendopeptidase activity; ISS:UniProtKB. DR GO; GO:0042277; F:peptide binding; ISS:UniProtKB. DR GO; GO:0001786; F:phosphatidylserine binding; IEA:Ensembl. DR GO; GO:0042803; F:protein homodimerization activity; IEA:Ensembl. DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB. DR GO; GO:0150094; P:amyloid-beta clearance by cellular catabolic process; IEA:Ensembl. 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:0007611; P:learning or memory; IEA:Ensembl. DR GO; GO:0061837; P:neuropeptide processing; IEA:Ensembl. DR GO; GO:0006518; P:peptide metabolic process; ISS:UniProtKB. DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; IEA:Ensembl. DR GO; GO:0050769; P:positive regulation of neurogenesis; IEA:Ensembl. 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; 3.40.390.10; Collagenase (Catalytic Domain); 1. DR Gene3D; 1.10.1380.10; Neutral endopeptidase , domain2; 1. DR InterPro; IPR024079; MetalloPept_cat_dom_sf. 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:SF114; NEPRILYSIN; 1. DR PANTHER; PTHR11733; ZINC METALLOPROTEASE FAMILY M13 NEPRILYSIN-RELATED; 1. DR Pfam; PF01431; Peptidase_M13; 1. DR Pfam; PF05649; Peptidase_M13_N; 1. DR PRINTS; PR00786; NEPRILYSIN. DR SUPFAM; SSF55486; Metalloproteases ('zincins'), catalytic domain; 1. 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 //