MMEL1_MOUSE
ID MMEL1_MOUSE Reviewed; 765 AA.
AC Q9JLI3; Q3U495; Q9ERK2; Q9ERK3; Q9QZV6; Q9QZV7;
DT 05-SEP-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 130.
DE RecName: Full=Membrane metallo-endopeptidase-like 1;
DE EC=3.4.24.11;
DE AltName: Full=NEP2(m);
DE AltName: Full=Neprilysin II;
DE Short=NEPII;
DE AltName: Full=Neprilysin-2;
DE Short=NEP2;
DE Short=NL2;
DE AltName: Full=Neprilysin-like 1;
DE Short=NL-1;
DE AltName: Full=Neprilysin-like peptidase;
DE Short=NEPLP;
DE AltName: Full=Soluble secreted endopeptidase;
DE Contains:
DE RecName: Full=Membrane metallo-endopeptidase-like 1, soluble form;
DE AltName: Full=Neprilysin-2 secreted;
DE Short=NEP2(s);
GN Name=Mmel1; Synonyms=Nep2, Nl1, Sep;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, GLYCOSYLATION,
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Testis;
RX PubMed=10542292; DOI=10.1074/jbc.274.45.32469;
RA Ikeda K., Emoto N., Raharjo S.B., Nurhantari Y., Saiki K., Yokoyama M.,
RA Matsuo M.;
RT "Molecular identification and characterization of novel membrane-bound
RT metalloprotease, the soluble secreted form of which hydrolyzes a variety of
RT vasoactive peptides.";
RL J. Biol. Chem. 274:32469-32477(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), GLYCOSYLATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND MUTAGENESIS OF 62-LYS-ARG-63.
RC TISSUE=Testis;
RX PubMed=10749671; DOI=10.1042/0264-6021:3470419;
RA Ghaddar G., Ruchon A.F., Carpentier M., Marcinkiewicz M., Seidah N.G.,
RA Crine P., DesGroseillers L., Boileau G.;
RT "Molecular cloning and biochemical characterization of a new mouse testis
RT soluble zinc-metallopeptidase of the neprilysin family.";
RL Biochem. J. 347:419-429(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, AND ACTIVITY
RP REGULATION.
RX PubMed=11278416; DOI=10.1074/jbc.m008511200;
RA Shirotani K., Tsubuki S., Iwata N., Takaki Y., Harigaya W., Maruyama K.,
RA Kiryu-Seo S., Kiyama H., Iwata H., Tomita T., Iwatsubo T., Saido T.C.;
RT "Neprilysin degrades both amyloid beta peptides 1-40 and 1-42 most rapidly
RT and efficiently among thiorphan- and phosphoramidon-sensitive
RT endopeptidases.";
RL J. Biol. Chem. 276:21895-21901(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 64-765.
RC STRAIN=NOD;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [5]
RP DISRUPTION PHENOTYPE.
RX PubMed=15121861; DOI=10.1128/mcb.24.10.4428-4437.2004;
RA Carpentier M., Guillemette C., Bailey J.L., Boileau G., Jeannotte L.,
RA DesGroseillers L., Charron J.;
RT "Reduced fertility in male mice deficient in the zinc metallopeptidase
RT NL1.";
RL Mol. Cell. Biol. 24:4428-4437(2004).
CC -!- FUNCTION: Metalloprotease involved in sperm function, possibly by
CC modulating the processes of fertilization and early embryonic
CC development. Degrades a broad variety of small peptides with a
CC preference for peptides shorter than 3 kDa containing neutral bulky
CC aliphatic or aromatic amino acid residues. Shares the same substrate
CC specificity with MME and cleaves peptides at the same amide bond.
CC {ECO:0000269|PubMed:10542292, ECO:0000269|PubMed:11278416}.
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 -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250};
CC -!- ACTIVITY REGULATION: Inhibited by thiorphan and phosphoramidon.
CC {ECO:0000269|PubMed:11278416}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=18 uM for D-Ala(2)-Leu(5)-enkephalin
CC {ECO:0000269|PubMed:10749671};
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000269|PubMed:10542292}; Single-
CC pass type II membrane protein {ECO:0000269|PubMed:10542292}. Secreted
CC {ECO:0000269|PubMed:10542292}. Note=A secreted form produced by
CC proteolytic cleavage also exists.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=Beta;
CC IsoId=Q9JLI3-1; Sequence=Displayed;
CC Name=2; Synonyms=Alpha, Delta;
CC IsoId=Q9JLI3-2; Sequence=VSP_020290;
CC Name=3; Synonyms=Gamma;
CC IsoId=Q9JLI3-3; Sequence=VSP_020290, VSP_020291;
CC -!- TISSUE SPECIFICITY: Highly expressed in testis. Also expressed in
CC ovary. Weakly or not expressed in brain, lung, heart, liver, kidney,
CC adrenal gland and intestine. {ECO:0000269|PubMed:10542292}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:10542292,
CC ECO:0000269|PubMed:10749671}.
CC -!- DISRUPTION PHENOTYPE: Mice are viable and develop normally. However,
CC males produce smaller litters, indicating specific male fertility
CC problems. {ECO:0000269|PubMed:15121861}.
CC -!- SIMILARITY: Belongs to the peptidase M13 family. {ECO:0000255|PROSITE-
CC ProRule:PRU01233, ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAE32538.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AF157105; AAF13152.1; -; mRNA.
DR EMBL; AF157106; AAF13153.1; -; mRNA.
DR EMBL; AF176569; AAF69247.1; -; mRNA.
DR EMBL; AF302075; AAG18446.1; -; mRNA.
DR EMBL; AF302076; AAG18447.1; -; mRNA.
DR EMBL; AF302077; AAG18448.1; -; mRNA.
DR EMBL; AK154366; BAE32538.1; ALT_INIT; mRNA.
DR RefSeq; NP_038811.2; NM_013783.2.
DR AlphaFoldDB; Q9JLI3; -.
DR SMR; Q9JLI3; -.
DR STRING; 10090.ENSMUSP00000101259; -.
DR MEROPS; M13.008; -.
DR GlyGen; Q9JLI3; 5 sites.
DR iPTMnet; Q9JLI3; -.
DR PhosphoSitePlus; Q9JLI3; -.
DR MaxQB; Q9JLI3; -.
DR PaxDb; Q9JLI3; -.
DR PRIDE; Q9JLI3; -.
DR ProteomicsDB; 291470; -. [Q9JLI3-1]
DR ProteomicsDB; 291471; -. [Q9JLI3-2]
DR ProteomicsDB; 291472; -. [Q9JLI3-3]
DR DNASU; 27390; -.
DR GeneID; 27390; -.
DR KEGG; mmu:27390; -.
DR UCSC; uc008wcg.1; mouse. [Q9JLI3-1]
DR CTD; 79258; -.
DR MGI; MGI:1351603; Mmel1.
DR eggNOG; KOG3624; Eukaryota.
DR InParanoid; Q9JLI3; -.
DR OrthoDB; 282463at2759; -.
DR BRENDA; 3.4.24.B14; 3474.
DR BioGRID-ORCS; 27390; 6 hits in 73 CRISPR screens.
DR ChiTaRS; Mmel1; mouse.
DR PRO; PR:Q9JLI3; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q9JLI3; protein.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:MGI.
DR GO; GO:0005615; C:extracellular space; ISO:MGI.
DR GO; GO:0005794; C:Golgi apparatus; IDA:MGI.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0004175; F:endopeptidase activity; ISO:MGI.
DR GO; GO:0004222; F:metalloendopeptidase activity; ISS:MGI.
DR GO; GO:0008270; F:zinc ion binding; ISO:MGI.
DR GO; GO:0016485; P:protein processing; IBA:GO_Central.
DR GO; GO:0006508; P:proteolysis; ISO:MGI.
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; IPR029735; MMEL1.
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:SF141; PTHR11733:SF141; 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 Alternative splicing; Coiled coil; Disulfide bond; Glycoprotein; Hydrolase;
KW Membrane; Metal-binding; Metalloprotease; Protease; Reference proteome;
KW Secreted; Signal-anchor; Transmembrane; Transmembrane helix; Zinc.
FT CHAIN 1..765
FT /note="Membrane metallo-endopeptidase-like 1"
FT /id="PRO_0000248417"
FT CHAIN 63..765
FT /note="Membrane metallo-endopeptidase-like 1, soluble form"
FT /evidence="ECO:0000305"
FT /id="PRO_0000248418"
FT TOPO_DOM 1..19
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 20..40
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 41..765
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT DOMAIN 74..765
FT /note="Peptidase M13"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT COILED 523..549
FT /evidence="ECO:0000255"
FT ACT_SITE 600
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT ACT_SITE 666
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT BINDING 121
FT /ligand="a peptide"
FT /ligand_id="ChEBI:CHEBI:60466"
FT /ligand_note="substrate"
FT /evidence="ECO:0000250"
FT BINDING 599
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 603
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 662
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT SITE 62..63
FT /note="Cleavage"
FT /evidence="ECO:0000305"
FT CARBOHYD 163
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 279
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 303
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 336
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 694
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 75..80
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 98..750
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 106..710
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 161..425
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 636..762
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT VAR_SEQ 41..63
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:10542292,
FT ECO:0000303|PubMed:11278416"
FT /id="VSP_020290"
FT VAR_SEQ 330
FT /note="F -> FGLKDRVSLCSPGCPGTHSVDQAGLELGNPPASDSRVL (in
FT isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_020291"
FT MUTAGEN 62..63
FT /note="KR->NG: Abolishes formation the soluble form."
FT /evidence="ECO:0000269|PubMed:10749671"
FT CONFLICT 189
FT /note="M -> L (in Ref. 1; AAF13152/AAF13153)"
FT /evidence="ECO:0000305"
FT CONFLICT 264
FT /note="L -> P (in Ref. 1; AAF13152/AAF13153)"
FT /evidence="ECO:0000305"
FT CONFLICT 659
FT /note="T -> S (in Ref. 1; AAF13152/AAF13153)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 765 AA; 88700 MW; D3662F1CE5B957F7 CRC64;
MVERAGWCRK KSPGFVEYGL MVLLLLLLGA IVTLGVFYSI GKQLPLLTSL LHFSWDERTV
VKRALRDSSL KSDICTTPSC VIAAARILEN MDQSRNPCEN FYQYACGGWL RHHVIPETNS
RYSVFDILRD ELEVILKGVL EDSTSQHRPA VEKAKTLYRS CMNQSVIEKR DSEPLLSVLK
MVGGWPVAMD KWNETMGLKW ELERQLAVLN SQFNRRVLID LFIWNDDQNS SRHVIYIDQP
TLGMPSREYY FQEDNNHKVR KAYLEFMTSV ATMLRKDQNL SKESAMVREE MAEVLELETH
LANATVPQEK RHDVTALYHR MDLMELQERF GLKGFNWTLF IQNVLSSVEV ELFPDEEVVV
YGIPYLENLE DIIDSYSART MQNYLVWRLV LDRIGSLSQR FKEARVDYRK ALYGTTVEEV
RWRECVSYVN SNMESAVGSL YIKRAFSKDS KSTVRELIEK IRSVFVDNLD ELNWMDEESK
KKAQEKAMNI REQIGYPDYI LEDNNKHLDE EYSSLTFYED LYFENGLQNL KNNAQRSLKK
LREKVDQNLW IIGAAVVNAF YSPNRNQIVF PAGILQPPFF SKDQPQSLNF GGIGMVIGHE
ITHGFDDNGR NFDKNGNMLD WWSNFSARHF QQQSQCMIYQ YGNFSWELAD NQNVNGFSTL
GENIADNGGV RQAYKAYLRW LADGGKDQRL PGLNLTYAQL FFINYAQVWC GSYRPEFAVQ
SIKTDVHSPL KYRVLGSLQN LPGFSEAFHC PRGSPMHPMK RCRIW
