NEP3_DROME
ID NEP3_DROME Reviewed; 786 AA.
AC Q9W5Y0; Q8SWS1;
DT 25-OCT-2017, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2002, sequence version 2.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=Neprilysin-3 {ECO:0000303|PubMed:24395329};
DE EC=3.4.24.11 {ECO:0000250|UniProtKB:Q8T062};
GN Name=Nep3 {ECO:0000303|PubMed:24395329, ECO:0000312|FlyBase:FBgn0031081};
GN ORFNames=CG9565 {ECO:0000312|FlyBase:FBgn0031081};
OS Drosophila melanogaster (Fruit fly).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC Drosophilidae; Drosophila; Sophophora.
OX NCBI_TaxID=7227 {ECO:0000312|Proteomes:UP000000803};
RN [1] {ECO:0000312|Proteomes:UP000000803}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Berkeley {ECO:0000312|Proteomes:UP000000803};
RX PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA Venter J.C.;
RT "The genome sequence of Drosophila melanogaster.";
RL Science 287:2185-2195(2000).
RN [2] {ECO:0000312|Proteomes:UP000000803}
RP GENOME REANNOTATION.
RC STRAIN=Berkeley {ECO:0000312|Proteomes:UP000000803};
RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT review.";
RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN [3] {ECO:0000312|EMBL:AAM12295.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Berkeley {ECO:0000312|EMBL:AAM12295.1};
RC TISSUE=Embryo {ECO:0000312|EMBL:AAM12295.1};
RX PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080;
RA Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A.,
RA Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M.,
RA Celniker S.E.;
RT "A Drosophila full-length cDNA resource.";
RL Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002).
RN [4] {ECO:0000312|EMBL:AEW12887.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Carlson J., Booth B., Frise E., Park S., Wan K., Yu C., Celniker S.;
RL Submitted (DEC-2011) to the EMBL/GenBank/DDBJ databases.
RN [5] {ECO:0000305}
RP DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=24395329; DOI=10.1534/genetics.113.160945;
RA Sitnik J.L., Francis C., Hens K., Huybrechts R., Wolfner M.F.,
RA Callaerts P.;
RT "Neprilysins: an evolutionarily conserved family of metalloproteases that
RT play important roles in reproduction in Drosophila.";
RL Genetics 196:781-797(2014).
RN [6] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=27629706; DOI=10.1523/jneurosci.3730-15.2016;
RA Turrel O., Lampin-Saint-Amaux A., Preat T., Goguel V.;
RT "Drosophila neprilysins are involved in middle-term and long-term memory.";
RL J. Neurosci. 36:9535-9546(2016).
CC -!- FUNCTION: Metalloendoprotease which is required in the dorsal paired
CC medial neurons for the proper formation of long-term (LTM) and middle-
CC term memories (MTM). Also required in the mushroom body neurons where
CC it functions redundantly with neprilysins Nep2 and Nep4 in normal LTM
CC formation. {ECO:0000269|PubMed:27629706}.
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:Q8T062};
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:0000305}; Single-pass type II
CC membrane protein {ECO:0000305}.
CC -!- DEVELOPMENTAL STAGE: In embryos, expressed in the central nervous
CC system from stages 14 to 17. In third-instar larvae, expressed in the
CC brain, ventral ganglion and midgut. {ECO:0000269|PubMed:24395329}.
CC -!- DISRUPTION PHENOTYPE: RNAi-mediated knockdown in the dorsal paired
CC medial neurons impairs middle-term (MTM) and long-term memory (LTM),
CC but has no effect on normal aversion learning and anesthesia-resistant
CC memory (ARM) (PubMed:27629706). RNAi-mediated knockdown in all mushroom
CC body neurons has no effect on learning, ARM and LTM (PubMed:27629706).
CC However, simultaneous knockdown with Nep2 or Nep4 does impair LTM, and
CC simultaneous knockdown with both Nep2 and Nep4 results in a further
CC reduction in LTM formation (PubMed:27629706). Wild-type females mated
CC to males that undergo RNAi-mediated knockdown, lay the same number of
CC eggs and have a similar hatch rate to those mated to wild-type males
CC (PubMed:24395329). {ECO:0000269|PubMed:24395329,
CC ECO:0000269|PubMed:27629706}.
CC -!- SIMILARITY: Belongs to the peptidase M13 family. {ECO:0000255|PROSITE-
CC ProRule:PRU01233, ECO:0000305}.
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DR EMBL; AE014298; AAF45370.2; -; Genomic_DNA.
DR EMBL; AE014298; AFH07487.1; -; Genomic_DNA.
DR EMBL; AE014298; AFH07488.1; -; Genomic_DNA.
DR EMBL; AY095202; AAM12295.1; -; mRNA.
DR EMBL; BT132915; AEW12887.1; -; mRNA.
DR RefSeq; NP_001245775.1; NM_001258846.1.
DR RefSeq; NP_001245776.1; NM_001258847.2.
DR RefSeq; NP_523417.2; NM_078693.3.
DR AlphaFoldDB; Q9W5Y0; -.
DR SMR; Q9W5Y0; -.
DR IntAct; Q9W5Y0; 7.
DR STRING; 7227.FBpp0300207; -.
DR MEROPS; M13.A14; -.
DR GlyGen; Q9W5Y0; 11 sites.
DR PaxDb; Q9W5Y0; -.
DR DNASU; 33005; -.
DR EnsemblMetazoa; FBtr0070000; FBpp0070000; FBgn0031081.
DR EnsemblMetazoa; FBtr0307554; FBpp0300206; FBgn0031081.
DR EnsemblMetazoa; FBtr0307555; FBpp0300207; FBgn0031081.
DR GeneID; 33005; -.
DR KEGG; dme:Dmel_CG9565; -.
DR UCSC; CG9565-RA; d. melanogaster.
DR CTD; 33005; -.
DR FlyBase; FBgn0031081; Nep3.
DR VEuPathDB; VectorBase:FBgn0031081; -.
DR eggNOG; KOG3624; Eukaryota.
DR GeneTree; ENSGT00940000166608; -.
DR HOGENOM; CLU_006187_8_1_1; -.
DR InParanoid; Q9W5Y0; -.
DR OMA; FGWAQVW; -.
DR OrthoDB; 282463at2759; -.
DR PhylomeDB; Q9W5Y0; -.
DR Reactome; R-DME-2022377; Metabolism of Angiotensinogen to Angiotensins.
DR Reactome; R-DME-6798695; Neutrophil degranulation.
DR SignaLink; Q9W5Y0; -.
DR BioGRID-ORCS; 33005; 0 hits in 3 CRISPR screens.
DR GenomeRNAi; 33005; -.
DR PRO; PR:Q9W5Y0; -.
DR Proteomes; UP000000803; Chromosome X.
DR Bgee; FBgn0031081; Expressed in brain and 14 other tissues.
DR ExpressionAtlas; Q9W5Y0; baseline and differential.
DR GO; GO:0016021; C:integral component of membrane; ISM:FlyBase.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004222; F:metalloendopeptidase activity; IEA:UniProtKB-EC.
DR GO; GO:0008237; F:metallopeptidase activity; ISM:FlyBase.
DR GO; GO:0016486; P:peptide hormone processing; ISS:FlyBase.
DR GO; GO:0016485; P:protein processing; IBA:GO_Central.
DR GO; GO:0006508; P:proteolysis; ISM:FlyBase.
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; 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 Pfam; PF01431; Peptidase_M13; 1.
DR Pfam; PF05649; Peptidase_M13_N; 1.
DR PRINTS; PR00786; NEPRILYSIN.
DR PROSITE; PS51885; NEPRILYSIN; 1.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 2: Evidence at transcript level;
KW Cell membrane; Disulfide bond; Glycoprotein; Hydrolase; Membrane;
KW Metal-binding; Metalloprotease; Protease; Reference proteome;
KW Signal-anchor; Transmembrane; Transmembrane helix; Zinc.
FT CHAIN 1..786
FT /note="Neprilysin-3"
FT /id="PRO_0000441992"
FT TOPO_DOM 1..52
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 53..73
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 74..786
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT DOMAIN 102..786
FT /note="Peptidase M13"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT ACT_SITE 623
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT ACT_SITE 686
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT BINDING 622
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 626
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 682
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT CARBOHYD 216
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 226
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 256
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 279
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 305
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 325
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 356
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 388
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 496
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 569
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 715
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT DISULFID 103..108
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 126..771
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 134..731
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 190..450
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 659..783
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT CONFLICT 49
FT /note="K -> R (in Ref. 3; AAM12295)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 786 AA; 89759 MW; 7CC2E708D0C042AF CRC64;
MTRYKQTEFT EDDSSSIGGI QLNEATGHTG MQIRYHTARA TWNWRSRNKT EKWLLITTFV
MAITIFTLLI VLFTDGGSSD ATKHVLHVQP HQKDCPSGNE LPCLNKHCIF ASSEILKSID
VTVDPCDDFY GYSCNQWIKN NPIPEGKSTW GTFGKLEQMN QLIIRNVLEK PAKSFKSDAE
RKAKVYYESC LDADEHMEKL GAKPMNDLLL QIGGWNVTKS GYNVANWTMG HTLKILHNKY
NFNCLFGWAI GEDDKNSSRH VIQIDQGGLT LPTADYYNNK TDNHRKVLNE YIEYMTKVCV
LLGANESDAR AQMIGVINFE KKLANITIPL EDRRNEEAMY HPMQLRQLSK LAPFLNWTDH
FDNAMQMVGR RVTDDEVVVV YAPDFLKNLS DIILKMEQTE EGKITLNNYL VWQAVRTLTS
CLSKPFRDAY KGVRKALMGS DGGEEIWRYC VSDTNNVVGF AVGAIFVRQA FHGESKPAAE
QMIAEIREAF KMNLQNLTWV DKQTREKAIE KANQISDMIG FPDYILDPVE LDKKYAELNI
TPNAYFENNI QVAIYNLKSN LKRLDQPVNK TNWGMTPQTV NAYYTPTKNQ IVFPAGILQT
PFFDINNPKS LNFGAMGVVM GHELTHAFDD QGREYDKFGN INRWWDSKSI ERFNEKSECI
ARQYSGYKMN GRTLNGKQTL GENIADNGGL KAAYHAYQRT KSDRDVDILK LPGLNLTHSQ
LFFVSFAQVW CSSTTDETNL LQMEKDPHSP SQFRVIGTLS NMKEFAEVFQ CKPGKRMNPT
EKCEVW
