NEP_HUMAN
ID NEP_HUMAN Reviewed; 750 AA.
AC P08473; A8K6U6; D3DNJ9; Q3MIX4;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 03-AUG-2022, entry version 241.
DE RecName: Full=Neprilysin {ECO:0000303|PubMed:15283675};
DE EC=3.4.24.11 {ECO:0000269|PubMed:15283675, ECO:0000269|PubMed:27588448, ECO:0000269|PubMed:6208535, ECO:0000269|PubMed:6349683, ECO:0000269|PubMed:8168535};
DE AltName: Full=Atriopeptidase;
DE AltName: Full=Common acute lymphocytic leukemia antigen;
DE Short=CALLA;
DE AltName: Full=Enkephalinase {ECO:0000303|PubMed:3162217};
DE AltName: Full=Neutral endopeptidase 24.11 {ECO:0000303|PubMed:2528730};
DE Short=NEP;
DE Short=Neutral endopeptidase;
DE AltName: Full=Skin fibroblast elastase;
DE Short=SFE;
DE AltName: CD_antigen=CD10 {ECO:0000303|PubMed:22766194};
GN Name=MME {ECO:0000303|PubMed:27588448, ECO:0000312|HGNC:HGNC:7154};
GN Synonyms=EPN;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Kidney;
RX PubMed=2971756; DOI=10.1084/jem.168.4.1247;
RA Letarte M., Vera S., Tran R., Addis J.B.L., Onizuka R.J., Quackenbush E.J.,
RA Jongeneel C.V., McInnes R.R.;
RT "Common acute lymphocytic leukemia antigen is identical to neutral
RT endopeptidase.";
RL J. Exp. Med. 168:1247-1253(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2968607; DOI=10.1073/pnas.85.13.4819;
RA Shipp M.A., Richardson N.E., Sayre P.H., Brown N.R., Masteller E.L.,
RA Clayton L.K., Ritz J., Reinherz E.L.;
RT "Molecular cloning of the common acute lymphoblastic leukemia antigen
RT (CALLA) identifies a type II integral membrane protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:4819-4823(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2528730; DOI=10.1073/pnas.86.18.7103;
RA D'Adamio L., Shipp M.A., Masteller E.L., Reinherz E.L.;
RT "Organization of the gene encoding common acute lymphoblastic leukemia
RT antigen (neutral endopeptidase 24.11): multiple miniexons and separate 5'
RT untranslated regions.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:7103-7107(1989).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G);
RL Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3-750.
RC TISSUE=Placenta;
RX PubMed=3162217; DOI=10.1016/0014-5793(88)80828-7;
RA Malfroy B., Kuang W.-J., Seeburg P.H., Mason A.J., Schofield P.R.;
RT "Molecular cloning and amino acid sequence of human enkephalinase (neutral
RT endopeptidase).";
RL FEBS Lett. 229:206-210(1988).
RN [9]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=6349683; DOI=10.1021/bi00282a035;
RA Gafford J.T., Skidgel R.A., Erdoes E.G., Hersh L.B.;
RT "Human kidney 'enkephalinase', a neutral metalloendopeptidase that cleaves
RT active peptides.";
RL Biochemistry 22:3265-3271(1983).
RN [10]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=6208535; DOI=10.1016/0196-9781(84)90020-2;
RA Skidgel R.A., Engelbrecht S., Johnson A.R., Erdoes E.G.;
RT "Hydrolysis of substance p and neurotensin by converting enzyme and neutral
RT endopeptidase.";
RL Peptides 5:769-776(1984).
RN [11]
RP FUNCTION.
RX PubMed=2972276; DOI=10.1042/bj2540531;
RA Vanneste Y., Michel A., Dimaline R., Najdovski T., Deschodt-Lanckman M.;
RT "Hydrolysis of alpha-human atrial natriuretic peptide in vitro by human
RT kidney membranes and purified endopeptidase-24.11. Evidence for a novel
RT cleavage site.";
RL Biochem. J. 254:531-537(1988).
RN [12]
RP FUNCTION IN THE DEGRADATION OF ANF.
RX PubMed=2531377; DOI=10.1016/0196-9781(89)90131-9;
RA Yandle T.G., Brennan S.O., Espiner E.A., Nicholls M.G., Richards A.M.;
RT "Endopeptidase-24.11 in human plasma degrades atrial natriuretic factor
RT (ANF) to ANF(99-105/106-126).";
RL Peptides 10:891-894(1989).
RN [13]
RP ACTIVE SITE ASP-651, AND CATALYTIC ACTIVITY.
RX PubMed=8168535; DOI=10.1111/j.1432-1033.1994.tb18760.x;
RA Le Moual H., Dion N., Roques B.P., Crine P., Boileau G.;
RT "Asp650 is crucial for catalytic activity of neutral endopeptidase 24-11.";
RL Eur. J. Biochem. 221:475-480(1994).
RN [14]
RP GLYCOSYLATION AT ASN-145 AND ASN-285.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [15]
RP FUNCTION IN ANGIOTENSIN PEPTIDE METABOLISM, BIOPHYSICOCHEMICAL PROPERTIES,
RP AND CATALYTIC ACTIVITY.
RX PubMed=15283675; DOI=10.1042/bj20040634;
RA Rice G.I., Thomas D.A., Grant P.J., Turner A.J., Hooper N.M.;
RT "Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and
RT neprilysin in angiotensin peptide metabolism.";
RL Biochem. J. 383:45-51(2004).
RN [16]
RP FUNCTION.
RX PubMed=16254193; DOI=10.1373/clinchem.2005.057638;
RA Brandt I., Lambeir A.M., Ketelslegers J.M., Vanderheyden M., Scharpe S.,
RA De Meester I.;
RT "Dipeptidyl-peptidase IV converts intact B-type natriuretic peptide into
RT its des-SerPro form.";
RL Clin. Chem. 52:82-87(2006).
RN [17]
RP FUNCTION, ACTIVITY REGULATION, AND INHIBITION BY OPIORPHIN.
RX PubMed=17101991; DOI=10.1073/pnas.0605865103;
RA Wisner A., Dufour E., Messaoudi M., Nejdi A., Marcel A., Ungeheuer M.-N.,
RA Rougeot C.;
RT "Human opiorphin, a natural antinociceptive modulator of opioid-dependent
RT pathways.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:17979-17984(2006).
RN [18]
RP IDENTIFICATION AS SKIN FIBROBLAST ELASTASE, FUNCTION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=20876573; DOI=10.1074/jbc.m110.161547;
RA Morisaki N., Moriwaki S., Sugiyama-Nakagiri Y., Haketa K., Takema Y.,
RA Imokawa G.;
RT "Neprilysin is identical to skin fibroblast elastase: its role in skin
RT aging and UV responses.";
RL J. Biol. Chem. 285:39819-39827(2010).
RN [19]
RP MYRISTOYLATION AT GLY-2.
RX PubMed=19756956; DOI=10.1007/s11010-009-0253-8;
RA Zheng R., Horiguchi A., Iida K., Lee J., Shen R., Goodman O.B. Jr.,
RA Nanus D.M.;
RT "Neutral endopeptidase is a myristoylated protein.";
RL Mol. Cell. Biochem. 335:173-180(2010).
RN [20]
RP GLYCOSYLATION AT ASN-628.
RX PubMed=22766194; DOI=10.1016/j.bbagen.2012.06.017;
RA Sato B., Katagiri Y.U., Iijima K., Yamada H., Ito S., Kawasaki N.,
RA Okita H., Fujimoto J., Kiyokawa N.;
RT "The human CD10 lacking an N-glycan at Asn(628) is deficient in surface
RT expression and neutral endopeptidase activity.";
RL Biochim. Biophys. Acta 1820:1715-1723(2012).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-4 AND SER-6, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [22]
RP FUNCTION, CATALYTIC ACTIVITY, INVOLVEMENT IN CMT2T, VARIANTS CMT2T ALA-12;
RP CYS-347; PRO-348 AND ASP-422, AND CHARACTERIZATION OF VARIANTS CMT2T
RP CYS-347 AND ASP-422.
RX PubMed=27588448; DOI=10.1016/j.ajhg.2016.07.008;
RA Auer-Grumbach M., Toegel S., Schabhuettl M., Weinmann D., Chiari C.,
RA Bennett D.L., Beetz C., Klein D., Andersen P.M., Boehme I., Fink-Puches R.,
RA Gonzalez M., Harms M.B., Motley W., Reilly M.M., Renner W.,
RA Rudnik-Schoeneborn S., Schlotter-Weigel B., Themistocleous A.C.,
RA Weishaupt J.H., Ludolph A.C., Wieland T., Tao F., Abreu L., Windhager R.,
RA Zitzelsberger M., Strom T.M., Walther T., Scherer S.S., Zuechner S.,
RA Martini R., Senderek J.;
RT "Rare variants in MME, encoding metalloprotease neprilysin, are linked to
RT late-onset autosomal-dominant axonal polyneuropathies.";
RL Am. J. Hum. Genet. 99:607-623(2016).
RN [23]
RP INVOLVEMENT IN CMT2T, VARIANTS CMT2T CYS-411 DEL AND ARG-621, VARIANT
RP HIS-497, AND CHARACTERIZATION OF VARIANT CMT2T ARG-621.
RX PubMed=26991897; DOI=10.1002/ana.24612;
RA Higuchi Y., Hashiguchi A., Yuan J., Yoshimura A., Mitsui J., Ishiura H.,
RA Tanaka M., Ishihara S., Tanabe H., Nozuma S., Okamoto Y., Matsuura E.,
RA Ohkubo R., Inamizu S., Shiraishi W., Yamasaki R., Ohyagi Y., Kira J.,
RA Oya Y., Yabe H., Nishikawa N., Tobisawa S., Matsuda N., Masuda M.,
RA Kugimoto C., Fukushima K., Yano S., Yoshimura J., Doi K., Nakagawa M.,
RA Morishita S., Tsuji S., Takashima H.;
RT "Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease
RT type 2.";
RL Ann. Neurol. 79:659-672(2016).
RN [24]
RP INVOLVEMENT IN SCA43, AND VARIANT SCA43 TYR-143.
RX PubMed=27583304; DOI=10.1212/nxg.0000000000000094;
RA Depondt C., Donatello S., Rai M., Wang F.C., Manto M., Simonis N.,
RA Pandolfo M.;
RT "MME mutation in dominant spinocerebellar ataxia with neuropathy (SCA43).";
RL Neurol. Genet. 2:E94-E94(2016).
RN [25]
RP ACTIVITY REGULATION.
RX PubMed=26931059; DOI=10.1038/srep22413;
RA Smith A.I., Rajapakse N.W., Kleifeld O., Lomonte B., Sikanyika N.L.,
RA Spicer A.J., Hodgson W.C., Conroy P.J., Small D.H., Kaye D.M.,
RA Parkington H.C., Whisstock J.C., Kuruppu S.;
RT "N-terminal domain of Bothrops asper Myotoxin II enhances the activity of
RT endothelin converting enzyme-1 and neprilysin.";
RL Sci. Rep. 6:22413-22413(2016).
RN [26]
RP ERRATUM OF PUBMED:26931059.
RX PubMed=27102936; DOI=10.1038/srep24333;
RA Smith A.I., Rajapakse N.W., Kleifeld O., Lomonte B., Sikanyika N.L.,
RA Spicer A.J., Hodgson W.C., Conroy P.J., Small D.H., Kaye D.M.,
RA Parkington H.C., Whisstock J.C., Kuruppu S.;
RT "Corrigendum: N-terminal domain of Bothrops asper Myotoxin II enhances the
RT activity of endothelin converting enzyme-1 and neprilysin.";
RL Sci. Rep. 6:24333-24333(2016).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS), AND GLYCOSYLATION AT ASN-145;
RP ASN-325 AND ASN-628.
RX PubMed=10669592; DOI=10.1006/jmbi.1999.3492;
RA Oefner C., D'Arcy A., Hennig M., Winkler F.K., Dale G.E.;
RT "Structure of human neutral endopeptidase (Neprilysin) complexed with
RT phosphoramidon.";
RL J. Mol. Biol. 296:341-349(2000).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 55-750 IN COMPLEXES WITH ZINC
RP IONS AND SYNTHETIC INHIBITORS, DISULFIDE BONDS, COFACTOR, AND GLYCOSYLATION
RP AT ASN-145; ASN-325 AND ASN-628.
RX PubMed=14747736; DOI=10.1107/s0907444903027410;
RA Oefner C., Roques B.P., Fournie-Zaluski M.-C., Dale G.E.;
RT "Structural analysis of neprilysin with various specific and potent
RT inhibitors.";
RL Acta Crystallogr. D 60:392-396(2004).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) OF 55-750 IN COMPLEX WITH ZINC IONS
RP AND THE SYNTHETIC INHIBITOR MCB3937, DISULFIDE BONDS, COFACTOR, AND
RP GLYCOSYLATION AT ASN-145; ASN-325 AND ASN-628.
RX PubMed=17704566; DOI=10.1107/s0907444907036281;
RA Oefner C., Pierau S., Schulz H., Dale G.E.;
RT "Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV.";
RL Acta Crystallogr. D 63:975-981(2007).
CC -!- FUNCTION: Thermolysin-like specificity, but is almost confined on
CC acting on polypeptides of up to 30 amino acids (PubMed:6349683,
CC PubMed:6208535, PubMed:15283675, PubMed:8168535). Biologically
CC important in the destruction of opioid peptides such as Met- and Leu-
CC enkephalins by cleavage of a Gly-Phe bond (PubMed:6349683,
CC PubMed:17101991). Catalyzes cleavage of bradykinin, substance P and
CC neurotensin peptides (PubMed:6208535). Able to cleave angiotensin-1,
CC angiotensin-2 and angiotensin 1-9 (PubMed:6349683, PubMed:15283675).
CC Involved in the degradation of atrial natriuretic factor (ANF) and
CC brain natriuretic factor (BNP(1-32)) (PubMed:2531377, PubMed:2972276,
CC PubMed:16254193). Displays UV-inducible elastase activity toward skin
CC preelastic and elastic fibers (PubMed:20876573).
CC {ECO:0000269|PubMed:15283675, ECO:0000269|PubMed:17101991,
CC ECO:0000269|PubMed:20876573, ECO:0000269|PubMed:2531377,
CC ECO:0000269|PubMed:27588448, ECO:0000269|PubMed:2972276,
CC ECO:0000269|PubMed:6208535, ECO:0000269|PubMed:6349683}.
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:15283675, ECO:0000269|PubMed:27588448,
CC ECO:0000269|PubMed:6208535, ECO:0000269|PubMed:6349683,
CC ECO:0000269|PubMed:8168535};
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:0000269|PubMed:6208535};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:71460;
CC Evidence={ECO:0000269|PubMed:6208535};
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:0000269|PubMed:6208535};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:71468;
CC Evidence={ECO:0000269|PubMed:6208535};
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:0000269|PubMed:6208535};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:71476;
CC Evidence={ECO:0000269|PubMed:6208535};
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:0000269|PubMed:6208535};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:71480;
CC Evidence={ECO:0000269|PubMed:6208535};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:14747736, ECO:0000269|PubMed:17704566};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:14747736,
CC ECO:0000269|PubMed:17704566};
CC -!- ACTIVITY REGULATION: Inhibited in a dose dependent manner by opiorphin
CC (PubMed:17101991). Activated by K49-P1-20, a twenty-residue synthetic
CC peptide shortened from the snake B.asper myotoxin II (PubMed:26931059).
CC {ECO:0000269|PubMed:17101991, ECO:0000269|PubMed:26931059}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=55.1 uM for angiotensin-1 {ECO:0000269|PubMed:15283675};
CC KM=179 uM for angiotensin-2 {ECO:0000269|PubMed:15283675};
CC KM=111.4 uM for angiotensin 1-9 {ECO:0000269|PubMed:15283675};
CC -!- INTERACTION:
CC P08473; P05067: APP; NbExp=3; IntAct=EBI-353759, EBI-77613;
CC P08473; P21926: CD9; NbExp=6; IntAct=EBI-353759, EBI-4280101;
CC P08473; Q06787-7: FMR1; NbExp=3; IntAct=EBI-353759, EBI-25856644;
CC P08473; P08107: HSPA1B; NbExp=3; IntAct=EBI-353759, EBI-629985;
CC P08473; P04792: HSPB1; NbExp=4; IntAct=EBI-353759, EBI-352682;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:20876573};
CC Single-pass type II membrane protein {ECO:0000255}.
CC -!- PTM: Myristoylation is a determinant of membrane targeting.
CC {ECO:0000269|PubMed:19756956}.
CC -!- PTM: Glycosylation at Asn-628 is necessary both for surface expression
CC and neutral endopeptidase activity. {ECO:0000269|PubMed:10669592,
CC ECO:0000269|PubMed:12754519, ECO:0000269|PubMed:14747736,
CC ECO:0000269|PubMed:17704566, ECO:0000269|PubMed:22766194}.
CC -!- DISEASE: Charcot-Marie-Tooth disease 2T (CMT2T) [MIM:617017]: An axonal
CC form of Charcot-Marie-Tooth disease, a disorder of the peripheral
CC nervous system, characterized by progressive weakness and atrophy,
CC initially of the peroneal muscles and later of the distal muscles of
CC the arms. Charcot-Marie-Tooth disease is classified in two main groups
CC on the basis of electrophysiologic properties and histopathology:
CC primary peripheral demyelinating neuropathies (designated CMT1 when
CC they are dominantly inherited) and primary peripheral axonal
CC neuropathies (CMT2). Neuropathies of the CMT2 group are characterized
CC by signs of axonal degeneration in the absence of obvious myelin
CC alterations, normal or slightly reduced nerve conduction velocities,
CC and progressive distal muscle weakness and atrophy.
CC {ECO:0000269|PubMed:26991897, ECO:0000269|PubMed:27588448}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Spinocerebellar ataxia 43 (SCA43) [MIM:617018]: A form of
CC spinocerebellar ataxia, a clinically and genetically heterogeneous
CC group of cerebellar disorders. Patients show progressive incoordination
CC of gait and often poor coordination of hands, speech and eye movements,
CC due to degeneration of the cerebellum with variable involvement of the
CC brainstem and spinal cord. SCA43 is a slowly progressive, autosomal
CC dominant form. {ECO:0000269|PubMed:27583304}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Important cell surface marker in the diagnostic of human
CC acute lymphocytic leukemia. {ECO:0000269|PubMed:2528730,
CC ECO:0000269|PubMed:2968607, ECO:0000269|PubMed:2971756}.
CC -!- SIMILARITY: Belongs to the peptidase M13 family. {ECO:0000255|PROSITE-
CC ProRule:PRU01233, ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA30157.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MMEID41386ch3q25.html";
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DR EMBL; Y00811; CAA68752.1; -; mRNA.
DR EMBL; J03779; AAA51915.1; -; mRNA.
DR EMBL; M26628; AAA52294.1; -; Genomic_DNA.
DR EMBL; M26607; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26608; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26609; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26610; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26611; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26612; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26613; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26614; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26615; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26616; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26617; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26618; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26619; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26620; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26621; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26622; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26623; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26624; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26625; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26626; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; M26627; AAA52294.1; JOINED; Genomic_DNA.
DR EMBL; AK291761; BAF84450.1; -; mRNA.
DR EMBL; EU326307; ACA05913.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78754.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78755.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78756.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78757.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78758.1; -; Genomic_DNA.
DR EMBL; BC101632; AAI01633.1; -; mRNA.
DR EMBL; BC101658; AAI01659.1; -; mRNA.
DR EMBL; X07166; CAA30157.1; ALT_INIT; mRNA.
DR CCDS; CCDS3172.1; -.
DR PIR; A41387; HYHUN.
DR RefSeq; NP_000893.2; NM_000902.3.
DR RefSeq; NP_009218.2; NM_007287.2.
DR RefSeq; NP_009219.2; NM_007288.2.
DR RefSeq; NP_009220.2; NM_007289.2.
DR RefSeq; XP_006713709.1; XM_006713646.3.
DR RefSeq; XP_006713710.1; XM_006713647.3.
DR RefSeq; XP_011511157.1; XM_011512855.2.
DR RefSeq; XP_011511158.1; XM_011512856.2.
DR RefSeq; XP_011511159.1; XM_011512857.2.
DR PDB; 1DMT; X-ray; 2.10 A; A=55-750.
DR PDB; 1R1H; X-ray; 1.95 A; A=55-750.
DR PDB; 1R1I; X-ray; 2.60 A; A=55-750.
DR PDB; 1R1J; X-ray; 2.35 A; A=55-750.
DR PDB; 1Y8J; X-ray; 2.25 A; A=55-750.
DR PDB; 2QPJ; X-ray; 2.05 A; A=55-750.
DR PDB; 2YB9; X-ray; 2.40 A; A=55-750.
DR PDB; 4CTH; X-ray; 2.15 A; A=52-750.
DR PDB; 5JMY; X-ray; 2.00 A; A/B=53-750.
DR PDB; 6GID; X-ray; 1.90 A; A=55-750.
DR PDB; 6SH1; X-ray; 2.10 A; AAA/CCC=55-750.
DR PDB; 6SH2; X-ray; 2.60 A; AAA=55-750.
DR PDB; 6SUK; X-ray; 1.75 A; A=52-750.
DR PDB; 6SVY; X-ray; 2.60 A; A=52-750.
DR PDB; 6THP; X-ray; 2.54 A; A/B=55-750.
DR PDB; 6XVP; X-ray; 2.65 A; A=52-750.
DR PDBsum; 1DMT; -.
DR PDBsum; 1R1H; -.
DR PDBsum; 1R1I; -.
DR PDBsum; 1R1J; -.
DR PDBsum; 1Y8J; -.
DR PDBsum; 2QPJ; -.
DR PDBsum; 2YB9; -.
DR PDBsum; 4CTH; -.
DR PDBsum; 5JMY; -.
DR PDBsum; 6GID; -.
DR PDBsum; 6SH1; -.
DR PDBsum; 6SH2; -.
DR PDBsum; 6SUK; -.
DR PDBsum; 6SVY; -.
DR PDBsum; 6THP; -.
DR PDBsum; 6XVP; -.
DR AlphaFoldDB; P08473; -.
DR SASBDB; P08473; -.
DR SMR; P08473; -.
DR BioGRID; 110455; 143.
DR IntAct; P08473; 104.
DR MINT; P08473; -.
DR STRING; 9606.ENSP00000418525; -.
DR BindingDB; P08473; -.
DR ChEMBL; CHEMBL1944; -.
DR DrugBank; DB08575; 2-[(1S)-1-BENZYL-2-SULFANYLETHYL]-1H-IMIDAZO[4,5-C]PYRIDIN-5-IUM.
DR DrugBank; DB02597; [2(R,S)-2-Sulfanylheptanoyl]-Phe-Ala.
DR DrugBank; DB00616; Candoxatril.
DR DrugBank; DB11623; Candoxatrilat.
DR DrugBank; DB05796; Daglutril.
DR DrugBank; DB06655; Liraglutide.
DR DrugBank; DB02558; N-(3-Phenyl-2-Sulfanylpropanoyl)Phenylalanylalanine.
DR DrugBank; DB02062; N-[3-[(1-Aminoethyl)(Hydroxy)Phosphoryl]-2-(1,1'-Biphenyl-4-Ylmethyl)Propanoyl]Alanine.
DR DrugBank; DB00886; Omapatrilat.
DR DrugBank; DB02557; Phosphoramidon.
DR DrugBank; DB09292; Sacubitril.
DR DrugBank; DB13928; Semaglutide.
DR DrugBank; DB08626; Thiorphan.
DR DrugCentral; P08473; -.
DR GuidetoPHARMACOLOGY; 1611; -.
DR MEROPS; M13.001; -.
DR CarbonylDB; P08473; -.
DR GlyConnect; 1541; 1 N-Linked glycan (1 site).
DR GlyGen; P08473; 6 sites, 1 N-linked glycan (1 site).
DR iPTMnet; P08473; -.
DR PhosphoSitePlus; P08473; -.
DR BioMuta; MME; -.
DR DMDM; 128062; -.
DR EPD; P08473; -.
DR jPOST; P08473; -.
DR MassIVE; P08473; -.
DR MaxQB; P08473; -.
DR PaxDb; P08473; -.
DR PeptideAtlas; P08473; -.
DR PRIDE; P08473; -.
DR ProteomicsDB; 52110; -.
DR Antibodypedia; 3658; 2430 antibodies from 55 providers.
DR DNASU; 4311; -.
DR Ensembl; ENST00000360490.7; ENSP00000353679.2; ENSG00000196549.13.
DR Ensembl; ENST00000460393.6; ENSP00000418525.1; ENSG00000196549.13.
DR Ensembl; ENST00000462745.5; ENSP00000419653.1; ENSG00000196549.13.
DR Ensembl; ENST00000473730.6; ENSP00000420542.2; ENSG00000196549.13.
DR Ensembl; ENST00000491026.6; ENSP00000418791.2; ENSG00000196549.13.
DR Ensembl; ENST00000492661.5; ENSP00000420389.1; ENSG00000196549.13.
DR Ensembl; ENST00000493237.5; ENSP00000417079.1; ENSG00000196549.13.
DR Ensembl; ENST00000675418.2; ENSP00000502021.2; ENSG00000196549.13.
DR Ensembl; ENST00000680057.1; ENSP00000505211.1; ENSG00000196549.13.
DR Ensembl; ENST00000680282.1; ENSP00000505690.1; ENSG00000196549.13.
DR GeneID; 4311; -.
DR KEGG; hsa:4311; -.
DR MANE-Select; ENST00000360490.7; ENSP00000353679.2; NM_007289.4; NP_009220.2.
DR UCSC; uc003fab.2; human.
DR CTD; 4311; -.
DR DisGeNET; 4311; -.
DR GeneCards; MME; -.
DR GeneReviews; MME; -.
DR HGNC; HGNC:7154; MME.
DR HPA; ENSG00000196549; Tissue enhanced (intestine, kidney).
DR MalaCards; MME; -.
DR MIM; 120520; gene.
DR MIM; 617017; phenotype.
DR MIM; 617018; phenotype.
DR neXtProt; NX_P08473; -.
DR OpenTargets; ENSG00000196549; -.
DR Orphanet; 495274; Charcot-Marie-Tooth disease type 2T.
DR Orphanet; 69063; Congenital membranous nephropathy due to fetomaternal anti-neutral endopeptidase alloimmunization.
DR Orphanet; 497757; MME-related autosomal dominant Charcot Marie Tooth disease type 2.
DR Orphanet; 497764; Spinocerebellar ataxia type 43.
DR PharmGKB; PA30864; -.
DR VEuPathDB; HostDB:ENSG00000196549; -.
DR eggNOG; KOG3624; Eukaryota.
DR GeneTree; ENSGT00940000156745; -.
DR HOGENOM; CLU_006187_8_0_1; -.
DR InParanoid; P08473; -.
DR OMA; GYPDEIM; -.
DR OrthoDB; 282463at2759; -.
DR PhylomeDB; P08473; -.
DR TreeFam; TF315192; -.
DR BRENDA; 3.4.24.11; 2681.
DR PathwayCommons; P08473; -.
DR Reactome; R-HSA-2022377; Metabolism of Angiotensinogen to Angiotensins.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR SignaLink; P08473; -.
DR SIGNOR; P08473; -.
DR BioGRID-ORCS; 4311; 8 hits in 1078 CRISPR screens.
DR ChiTaRS; MME; human.
DR EvolutionaryTrace; P08473; -.
DR GeneWiki; Neprilysin; -.
DR GenomeRNAi; 4311; -.
DR Pharos; P08473; Tclin.
DR PRO; PR:P08473; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; P08473; protein.
DR Bgee; ENSG00000196549; Expressed in jejunal mucosa and 144 other tissues.
DR ExpressionAtlas; P08473; baseline and differential.
DR Genevisible; P08473; HS.
DR GO; GO:0030424; C:axon; IGI:ARUK-UCL.
DR GO; GO:0005903; C:brush border; IDA:UniProtKB.
DR GO; GO:0009986; C:cell surface; NAS:ARUK-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:ARUK-UCL.
DR GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR GO; GO:0005769; C:early endosome; IDA:ARUK-UCL.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005925; C:focal adhesion; HDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; NAS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; NAS:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IDA:ARUK-UCL.
DR GO; GO:0044306; C:neuron projection terminus; ISS:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; IDA:ARUK-UCL.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0098793; C:presynapse; IGI:ARUK-UCL.
DR GO; GO:0030667; C:secretory granule membrane; TAS:Reactome.
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; IDA:ARUK-UCL.
DR GO; GO:1901612; F:cardiolipin binding; IDA:ARUK-UCL.
DR GO; GO:0004175; F:endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0008238; F:exopeptidase activity; IDA:BHF-UCL.
DR GO; GO:0004222; F:metalloendopeptidase activity; IDA:UniProtKB.
DR GO; GO:0070012; F:oligopeptidase activity; IEA:Ensembl.
DR GO; GO:0042277; F:peptide binding; ISS:UniProtKB.
DR GO; GO:0001786; F:phosphatidylserine binding; IDA:ARUK-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:ARUK-UCL.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0007568; P:aging; IEP:ARUK-UCL.
DR GO; GO:0097242; P:amyloid-beta clearance; IDA:ARUK-UCL.
DR GO; GO:0150094; P:amyloid-beta clearance by cellular catabolic process; IDA:ARUK-UCL.
DR GO; GO:0050435; P:amyloid-beta metabolic process; ISS:UniProtKB.
DR GO; GO:0010815; P:bradykinin catabolic process; IDA:UniProtKB.
DR GO; GO:0071345; P:cellular response to cytokine stimulus; IDA:UniProtKB.
DR GO; GO:0071492; P:cellular response to UV-A; IDA:UniProtKB.
DR GO; GO:0071493; P:cellular response to UV-B; IDA:UniProtKB.
DR GO; GO:0046449; P:creatinine metabolic process; IMP:UniProtKB.
DR GO; GO:0042447; P:hormone catabolic process; IDA:UniProtKB.
DR GO; GO:0001822; P:kidney development; IEP:UniProtKB.
DR GO; GO:0007611; P:learning or memory; IGI:ARUK-UCL.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0061837; P:neuropeptide processing; IGI:ARUK-UCL.
DR GO; GO:0006518; P:peptide metabolic process; ISS:UniProtKB.
DR GO; GO:0001890; P:placenta development; IEA:Ensembl.
DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; IEA:Ensembl.
DR GO; GO:0050769; P:positive regulation of neurogenesis; IGI:ARUK-UCL.
DR GO; GO:0030163; P:protein catabolic process; IEA:Ensembl.
DR GO; GO:0016485; P:protein processing; IBA:GO_Central.
DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR GO; GO:0090399; P:replicative senescence; IEP:UniProtKB.
DR GO; GO:0043627; P:response to estrogen; IEA:Ensembl.
DR GO; GO:0019233; P:sensory perception of pain; ISS:UniProtKB.
DR GO; GO:0010814; P:substance P catabolic process; IDA: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 3D-structure; Cell membrane; Charcot-Marie-Tooth disease; Disease variant;
KW Disulfide bond; Glycoprotein; Hydrolase; Lipoprotein; Membrane;
KW Metal-binding; Metalloprotease; Myristate; Neurodegeneration; Neuropathy;
KW Phosphoprotein; Protease; Reference proteome; Signal-anchor;
KW Spinocerebellar ataxia; Transmembrane; Transmembrane helix; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT CHAIN 2..750
FT /note="Neprilysin"
FT /id="PRO_0000078213"
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 ECO:0000269|PubMed:8168535"
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 BINDING 588
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
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:0007744|PubMed:24275569"
FT MOD_RES 6
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT LIPID 2
FT /note="N-myristoyl glycine"
FT /evidence="ECO:0000269|PubMed:19756956"
FT CARBOHYD 145
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:10669592,
FT ECO:0000269|PubMed:12754519, ECO:0000269|PubMed:14747736,
FT ECO:0000269|PubMed:17704566"
FT CARBOHYD 285
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:12754519"
FT CARBOHYD 325
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:10669592,
FT ECO:0000269|PubMed:14747736, ECO:0000269|PubMed:17704566"
FT CARBOHYD 628
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:10669592,
FT ECO:0000269|PubMed:14747736, ECO:0000269|PubMed:17704566,
FT ECO:0000269|PubMed:22766194"
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 VARIANT 12
FT /note="D -> A (in CMT2T; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:27588448"
FT /id="VAR_077684"
FT VARIANT 143
FT /note="C -> Y (in SCA43; dbSNP:rs879255651)"
FT /evidence="ECO:0000269|PubMed:27583304"
FT /id="VAR_077685"
FT VARIANT 347
FT /note="Y -> C (in CMT2T; results in reduction of neprilysin
FT activity; dbSNP:rs138218277)"
FT /evidence="ECO:0000269|PubMed:27588448"
FT /id="VAR_077686"
FT VARIANT 348
FT /note="A -> P (in CMT2T; unknown pathological significance;
FT dbSNP:rs199567914)"
FT /evidence="ECO:0000269|PubMed:27588448"
FT /id="VAR_077687"
FT VARIANT 411
FT /note="Missing (in CMT2T; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:26991897"
FT /id="VAR_077688"
FT VARIANT 422
FT /note="A -> D (in CMT2T; late-onset form; results in
FT reduction of neprilysin activity; dbSNP:rs777476150)"
FT /evidence="ECO:0000269|PubMed:27588448"
FT /id="VAR_077689"
FT VARIANT 497
FT /note="Y -> H (in dbSNP:rs200308207)"
FT /evidence="ECO:0000269|PubMed:26991897"
FT /id="VAR_077690"
FT VARIANT 621
FT /note="C -> R (in CMT2T; decrease of protein expression;
FT dbSNP:rs879253752)"
FT /evidence="ECO:0000269|PubMed:26991897"
FT /id="VAR_077691"
FT CONFLICT 26
FT /note="P -> R (in Ref. 4; AAA51915)"
FT /evidence="ECO:0000305"
FT CONFLICT 44
FT /note="T -> R (in Ref. 4; AAA51915)"
FT /evidence="ECO:0000305"
FT CONFLICT 81
FT /note="T -> R (in Ref. 4; AAA51915)"
FT /evidence="ECO:0000305"
FT CONFLICT 304
FT /note="T -> R (in Ref. 4; AAA51915)"
FT /evidence="ECO:0000305"
FT HELIX 60..72
FT /evidence="ECO:0007829|PDB:6SUK"
FT TURN 79..81
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 83..94
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 102..105
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 106..122
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 131..144
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 146..151
FT /evidence="ECO:0007829|PDB:6SUK"
FT TURN 152..154
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 155..160
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 161..164
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 168..170
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 171..173
FT /evidence="ECO:0007829|PDB:1R1H"
FT HELIX 174..177
FT /evidence="ECO:0007829|PDB:6SUK"
FT TURN 178..181
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 184..195
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 200..208
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 211..220
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 225..228
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 229..233
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 236..238
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 239..259
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 266..286
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 290..293
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 296..299
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 302..304
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 305..311
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 316..319
FT /evidence="ECO:0007829|PDB:1R1H"
FT HELIX 323..331
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 332..334
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 343..347
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 349..359
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 364..379
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 380..382
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 385..389
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 392..399
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 407..418
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 420..431
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 436..457
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 459..461
FT /evidence="ECO:0007829|PDB:6GID"
FT HELIX 463..475
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 477..481
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 485..488
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 490..496
FT /evidence="ECO:0007829|PDB:6SUK"
FT TURN 497..499
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 507..524
FT /evidence="ECO:0007829|PDB:6SUK"
FT TURN 525..527
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 545..547
FT /evidence="ECO:0007829|PDB:6SUK"
FT TURN 548..551
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 552..556
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 557..559
FT /evidence="ECO:0007829|PDB:6SUK"
FT TURN 562..564
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 567..569
FT /evidence="ECO:0007829|PDB:2YB9"
FT HELIX 571..576
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 578..588
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 594..596
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 609..627
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 632..634
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 636..638
FT /evidence="ECO:0007829|PDB:2YB9"
FT TURN 641..644
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 645..669
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 682..692
FT /evidence="ECO:0007829|PDB:6SUK"
FT STRAND 696..698
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 700..709
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 715..724
FT /evidence="ECO:0007829|PDB:6SUK"
FT HELIX 727..732
FT /evidence="ECO:0007829|PDB:6SUK"
SQ SEQUENCE 750 AA; 85514 MW; BCF3827C39898630 CRC64;
MGKSESQMDI TDINTPKPKK KQRWTPLEIS LSVLVLLLTI IAVTMIALYA TYDDGICKSS
DCIKSAARLI QNMDATTEPC TDFFKYACGG WLKRNVIPET SSRYGNFDIL RDELEVVLKD
VLQEPKTEDI VAVQKAKALY RSCINESAID SRGGEPLLKL LPDIYGWPVA TENWEQKYGA
SWTAEKAIAQ LNSKYGKKVL INLFVGTDDK NSVNHVIHID QPRLGLPSRD YYECTGIYKE
ACTAYVDFMI SVARLIRQEE RLPIDENQLA LEMNKVMELE KEIANATAKP EDRNDPMLLY
NKMTLAQIQN 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
