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 24-JAN-2024, entry version 249. 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, axonal, 2T (CMT2T) [MIM:617017]: CC An axonal form of Charcot-Marie-Tooth disease, a disorder of the CC peripheral nervous system, characterized by progressive weakness and CC atrophy, initially of the peroneal muscles and later of the distal CC muscles of the arms. Charcot-Marie-Tooth disease is classified in two CC main groups on the basis of electrophysiologic properties and CC histopathology: primary peripheral demyelinating neuropathies CC (designated CMT1 when they are dominantly inherited) and primary CC peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group CC are characterized by signs of axonal degeneration in the absence of CC obvious myelin alterations, normal or slightly reduced nerve conduction CC velocities, 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="https://atlasgeneticsoncology.org/gene/41386/MME"; 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; 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; 146. 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 GlyCosmos; P08473; 4 sites, 1 glycan. DR GlyGen; P08473; 6 sites, 1 N-linked glycan (1 site). DR iPTMnet; P08473; -. DR PhosphoSitePlus; P08473; -. DR SwissPalm; P08473; -. DR BioMuta; MME; -. DR DMDM; 128062; -. DR EPD; P08473; -. DR jPOST; P08473; -. DR MassIVE; P08473; -. DR MaxQB; P08473; -. DR PaxDb; 9606-ENSP00000418525; -. DR PeptideAtlas; P08473; -. DR ProteomicsDB; 52110; -. DR Antibodypedia; 3658; 2807 antibodies from 56 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 AGR; HGNC:7154; -. 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; 202716at2759; -. 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-5578768; Physiological factors. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR SignaLink; P08473; -. DR SIGNOR; P08473; -. DR BioGRID-ORCS; 4311; 9 hits in 1166 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 146 other cell types or 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:0016020; C: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; IPI:ARUK-UCL. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. 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; 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 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; uncertain 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; uncertain significance; FT dbSNP:rs199567914)" FT /evidence="ECO:0000269|PubMed:27588448" FT /id="VAR_077687" FT VARIANT 411 FT /note="Missing (in CMT2T; uncertain 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 //