NEP_DROME
ID NEP_DROME Reviewed; 849 AA.
AC Q9W436;
DT 25-OCT-2017, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2002, sequence version 2.
DT 03-AUG-2022, entry version 157.
DE RecName: Full=Neprilysin-1 {ECO:0000303|PubMed:24395329};
DE EC=3.4.24.11 {ECO:0000250|UniProtKB:Q8T062};
GN Name=Nep1 {ECO:0000303|PubMed:24395329, ECO:0000312|FlyBase:FBgn0029843};
GN ORFNames=CG5905 {ECO:0000312|FlyBase:FBgn0029843};
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:AAO39625.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Berkeley {ECO:0000312|EMBL:AAO39625.1};
RC TISSUE=Head {ECO:0000312|EMBL:AAO39625.1};
RA Stapleton M., Brokstein P., Hong L., Agbayani A., Carlson J., Champe M.,
RA Chavez C., Dorsett V., Dresnek D., Farfan D., Frise E., George R.,
RA Gonzalez M., Guarin H., Kronmiller B., Li P., Liao G., Miranda A.,
RA Mungall C.J., Nunoo J., Pacleb J., Paragas V., Park S., Patel S.,
RA Phouanenavong S., Wan K., Yu C., Lewis S.E., Rubin G.M., Celniker S.;
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [4] {ECO:0000305}
RP FUNCTION, TISSUE SPECIFICITY, 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 [5] {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 functions in fertility and memory
CC formation (PubMed:24395329, PubMed:27629706). Required in the dorsal
CC paired medial neurons and alpha/beta mushroom body neurons for the
CC proper formation of long-term and middle-term memories
CC (PubMed:27629706). Required in males to maximise egg-laying in female
CC mates and is also required in females for their fertility
CC (PubMed:24395329). {ECO:0000269|PubMed:24395329,
CC 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 -!- TISSUE SPECIFICITY: Expressed in the testicular tube, near and in the
CC seminal vesicles. In adults and third-instar larvae, expressed in the
CC midgut and in the mushroom bodies of the brain and neurons in the pars
CC intercerebralis. Also expressed in neurons of the ventral ganglion and
CC imaginal disks (wing and leg) of third-instar larvae. In stage 17
CC embryos, expressed in the peripheral nervous system, pharynx and
CC midgut. {ECO:0000269|PubMed:24395329}.
CC -!- DISRUPTION PHENOTYPE: RNAi-mediated knockdown females lay fewer eggs
CC and display a reduced hatch rate when mated to wild-type males, and
CC wild-type females lay fewer eggs when mated to RNAi-mediated knockdown
CC males (PubMed:24395329). 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 alpha/beta
CC mushroom body neurons impairs MTM and LTM (PubMed:27629706). RNAi-
CC mediated knockdown in all mushroom body neurons has no effect on
CC learning and ARM (PubMed:27629706). {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; AAF46123.2; -; Genomic_DNA.
DR EMBL; AE014298; AAF46124.2; -; Genomic_DNA.
DR EMBL; AE014298; AHN59396.1; -; Genomic_DNA.
DR EMBL; AE014298; AHN59397.1; -; Genomic_DNA.
DR EMBL; BT003622; AAO39625.1; -; mRNA.
DR RefSeq; NP_001284925.1; NM_001297996.1.
DR RefSeq; NP_001284926.1; NM_001297997.1.
DR RefSeq; NP_511056.2; NM_078501.3.
DR RefSeq; NP_727065.1; NM_167059.2.
DR AlphaFoldDB; Q9W436; -.
DR SMR; Q9W436; -.
DR STRING; 7227.FBpp0070837; -.
DR MEROPS; M13.A15; -.
DR GlyGen; Q9W436; 7 sites.
DR PaxDb; Q9W436; -.
DR PRIDE; Q9W436; -.
DR DNASU; 31547; -.
DR EnsemblMetazoa; FBtr0070872; FBpp0070837; FBgn0029843.
DR EnsemblMetazoa; FBtr0070873; FBpp0070838; FBgn0029843.
DR EnsemblMetazoa; FBtr0340032; FBpp0309046; FBgn0029843.
DR EnsemblMetazoa; FBtr0343930; FBpp0310420; FBgn0029843.
DR GeneID; 31547; -.
DR KEGG; dme:Dmel_CG5905; -.
DR UCSC; CG5905-RA; d. melanogaster.
DR CTD; 31547; -.
DR FlyBase; FBgn0029843; Nep1.
DR VEuPathDB; VectorBase:FBgn0029843; -.
DR eggNOG; KOG3624; Eukaryota.
DR GeneTree; ENSGT00940000164877; -.
DR HOGENOM; CLU_006187_4_0_1; -.
DR InParanoid; Q9W436; -.
DR OMA; APRNHDA; -.
DR OrthoDB; 282463at2759; -.
DR PhylomeDB; Q9W436; -.
DR Reactome; R-DME-2022377; Metabolism of Angiotensinogen to Angiotensins.
DR Reactome; R-DME-6798695; Neutrophil degranulation.
DR BioGRID-ORCS; 31547; 0 hits in 3 CRISPR screens.
DR GenomeRNAi; 31547; -.
DR PRO; PR:Q9W436; -.
DR Proteomes; UP000000803; Chromosome X.
DR Bgee; FBgn0029843; Expressed in seminal fluid secreting gland and 19 other tissues.
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; IBA:GO_Central.
DR GO; GO:0008237; F:metallopeptidase activity; ISM:FlyBase.
DR GO; GO:0016485; P:protein processing; IBA:GO_Central.
DR GO; GO:0006508; P:proteolysis; ISS: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..849
FT /note="Neprilysin-1"
FT /id="PRO_0000441989"
FT TOPO_DOM 1..113
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 114..134
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 135..849
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT DOMAIN 172..849
FT /note="Peptidase M13"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT REGION 41..63
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 146..167
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 685
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT ACT_SITE 750
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT BINDING 684
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 688
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 746
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT CARBOHYD 309
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 326
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 393
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 589
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 599
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 709
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 778
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT DISULFID 173..178
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 196..834
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 204..794
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 260..512
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 721..846
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
SQ SEQUENCE 849 AA; 96534 MW; 8058B4FE82546DBA CRC64;
MSQQHEATAA AAEKPLNNGY LQANAPLEEL SATVVSPLLG QQQVQHQAPH QMQQQQQQQQ
QNKLPTVVFL APDGSGGVGI QRGNPAQGNP GMVTGTGSHS DWLLKESQQR RRLLVLAIAF
TVLGAAIGAL AIYFASVHQR CHLYRLEPDN DDRPNGRWNQ DSGSAHEGQD NICMTQECVR
TAASLLSAMD LNSDPCEDFF QYACGTWNKM HPIPEDRSSI STFEVLSDQQ QVILRAVLEE
PIDERDNKAT IKAKTFFKSC MDIPQIRKIG TGRLKQVLQS LGGWPVIERN WSPPADLSVE
RLMGQLRLNY SEPVMIELYV GADDKNSSVN ILQMDQLQYA LPSRDYYLKE SSANDRRAYH
RYMTQVALLL GADPATAAAE LEKVVLFETQ LVNVSLPEAD RHDTSLVYRK MLLPELQELV
PEVQWQEYLQ AALGPGIPLQ EDEPLVTYGL HYLTEMGKIL AHTDRRVVHN YMLWRLVMSL
MSHMIDEYQR ERVEFRKILM GIQSERTRWS QCVEWTNKKL GVAVGALFIR DNFNQESKEV
ALEMIHTIRA AFNELLAEND WMDDETRAVA KEKADSMNER IGYPELLTNA TELEQEYVNL
TIVPDNFINN VLSILQWESE KMLRLLRQPV DKEKWTTEPA VVNAFYNPNK NDIVFPAGIL
QPLFYSQHFP KSLNYGGIGV VIGHEITHGF DDKGRQFDKE GNMMQWWNNA TIEAFRERTQ
CVIDQYSRYK INEVDMFMDG RMTQGENIAD NGGLKQAFRA YKKWETLHGR EQQLPGLNMT
HDQLFFLNYA QIWCGSMRPE DALTKIRSAV HSPGFVRVLG PLSNSRDFAS AYKCPLGSTM
NPAEKCSVW
