ID   MMEL1_HUMAN             Reviewed;         779 AA.
AC   Q495T6; B9DI79; Q495T7; Q495T8; Q5SZS6; Q96PH9;
DT   05-SEP-2006, integrated into UniProtKB/Swiss-Prot.
DT   05-SEP-2006, sequence version 2.
DT   27-MAR-2024, entry version 154.
DE   RecName: Full=Membrane metallo-endopeptidase-like 1;
DE            EC=3.4.24.11;
DE   AltName: Full=Membrane metallo-endopeptidase-like 2;
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   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=MELL1, MMEL2, NEP2;
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] (ISOFORM 1), AND TISSUE SPECIFICITY.
RX   PubMed=11560781; DOI=10.1089/104454901316976127;
RA   Bonvouloir N., Lemieux N., Crine P., Boileau G., DesGroseillers L.;
RT   "Molecular cloning, tissue distribution, and chromosomal localization of
RT   MMEL2, a gene coding for a novel human member of the neutral endopeptidase-
RT   24.11 family.";
RL   DNA Cell Biol. 20:493-498(2001).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16710414; DOI=10.1038/nature04727;
RA   Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA   Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA   Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA   Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA   Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA   Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA   Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA   Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA   Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA   Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA   Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA   Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA   Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA   Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA   Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA   Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA   Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA   Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA   McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA   Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA   Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA   Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA   Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA   Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA   White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA   Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA   Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA   Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT   "The DNA sequence and biological annotation of human chromosome 1.";
RL   Nature 441:315-321(2006).
RN   [3]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3), AND VARIANT
RP   THR-518.
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).
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 (By
CC       similarity). {ECO:0000250}.
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:0000250}.
CC   -!- SUBCELLULAR LOCATION: Membrane; Single-pass type II membrane protein.
CC       Secreted. Note=A secreted form produced by proteolytic cleavage also
CC       exists. {ECO:0000250}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1;
CC         IsoId=Q495T6-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q495T6-2; Sequence=VSP_020288, VSP_020289;
CC       Name=3;
CC         IsoId=Q495T6-3; Sequence=VSP_020287;
CC   -!- TISSUE SPECIFICITY: Predominantly expressed in testis. Weakly expressed
CC       in brain, kidney and heart. {ECO:0000269|PubMed:11560781}.
CC   -!- PTM: N-glycosylated. {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the peptidase M13 family. {ECO:0000255|PROSITE-
CC       ProRule:PRU01233, ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAI01028.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC       Sequence=AAI01031.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC       Sequence=AAL08942.1; Type=Frameshift; Evidence={ECO:0000305};
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DR   EMBL; AF336981; AAL08942.1; ALT_FRAME; mRNA.
DR   EMBL; AL139246; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL589746; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL831784; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471183; EAW56082.1; -; Genomic_DNA.
DR   EMBL; BC101027; AAI01028.2; ALT_INIT; mRNA.
DR   EMBL; BC101028; AAI01029.2; -; mRNA.
DR   EMBL; BC101029; AAI01030.1; -; mRNA.
DR   EMBL; BC101030; AAI01031.2; ALT_INIT; mRNA.
DR   CCDS; CCDS30569.2; -. [Q495T6-1]
DR   RefSeq; NP_258428.2; NM_033467.3. [Q495T6-1]
DR   RefSeq; XP_016857799.1; XM_017002310.1.
DR   AlphaFoldDB; Q495T6; -.
DR   SMR; Q495T6; -.
DR   BioGRID; 122609; 2.
DR   IntAct; Q495T6; 1.
DR   STRING; 9606.ENSP00000367668; -.
DR   BindingDB; Q495T6; -.
DR   ChEMBL; CHEMBL3638356; -.
DR   MEROPS; M13.008; -.
DR   GlyCosmos; Q495T6; 5 sites, No reported glycans.
DR   GlyGen; Q495T6; 5 sites.
DR   iPTMnet; Q495T6; -.
DR   PhosphoSitePlus; Q495T6; -.
DR   BioMuta; MMEL1; -.
DR   DMDM; 114150028; -.
DR   jPOST; Q495T6; -.
DR   MassIVE; Q495T6; -.
DR   PaxDb; 9606-ENSP00000367668; -.
DR   PeptideAtlas; Q495T6; -.
DR   ProteomicsDB; 61971; -. [Q495T6-1]
DR   ProteomicsDB; 61972; -. [Q495T6-2]
DR   ProteomicsDB; 61973; -. [Q495T6-3]
DR   Antibodypedia; 1624; 180 antibodies from 26 providers.
DR   DNASU; 79258; -.
DR   Ensembl; ENST00000378412.8; ENSP00000367668.3; ENSG00000142606.16. [Q495T6-1]
DR   Ensembl; ENST00000502556.5; ENSP00000422492.1; ENSG00000142606.16. [Q495T6-3]
DR   Ensembl; ENST00000504800.5; ENSP00000425477.1; ENSG00000142606.16. [Q495T6-2]
DR   Ensembl; ENST00000611357.4; ENSP00000484606.1; ENSG00000277131.4. [Q495T6-1]
DR   Ensembl; ENST00000621908.3; ENSP00000482173.1; ENSG00000277131.4. [Q495T6-3]
DR   Ensembl; ENST00000628503.2; ENSP00000486668.1; ENSG00000277131.4. [Q495T6-2]
DR   GeneID; 79258; -.
DR   KEGG; hsa:79258; -.
DR   MANE-Select; ENST00000378412.8; ENSP00000367668.3; NM_033467.4; NP_258428.2.
DR   UCSC; uc001ajy.3; human. [Q495T6-1]
DR   AGR; HGNC:14668; -.
DR   CTD; 79258; -.
DR   DisGeNET; 79258; -.
DR   GeneCards; MMEL1; -.
DR   HGNC; HGNC:14668; MMEL1.
DR   HPA; ENSG00000142606; Tissue enhanced (testis).
DR   MalaCards; MMEL1; -.
DR   MIM; 618104; gene.
DR   neXtProt; NX_Q495T6; -.
DR   OpenTargets; ENSG00000142606; -.
DR   Orphanet; 186; Primary biliary cholangitis.
DR   PharmGKB; PA30865; -.
DR   VEuPathDB; HostDB:ENSG00000142606; -.
DR   eggNOG; KOG3624; Eukaryota.
DR   GeneTree; ENSGT00940000157799; -.
DR   HOGENOM; CLU_006187_4_1_1; -.
DR   InParanoid; Q495T6; -.
DR   OMA; PVIERDW; -.
DR   OrthoDB; 202716at2759; -.
DR   PhylomeDB; Q495T6; -.
DR   TreeFam; TF315192; -.
DR   BRENDA; 3.4.24.B14; 2681.
DR   PathwayCommons; Q495T6; -.
DR   SignaLink; Q495T6; -.
DR   BioGRID-ORCS; 79258; 14 hits in 1150 CRISPR screens.
DR   ChiTaRS; MMEL1; human.
DR   GenomeRNAi; 79258; -.
DR   Pharos; Q495T6; Tchem.
DR   PRO; PR:Q495T6; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   RNAct; Q495T6; Protein.
DR   Bgee; ENSG00000142606; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 91 other cell types or tissues.
DR   ExpressionAtlas; Q495T6; baseline and differential.
DR   GO; GO:0005615; C:extracellular space; IDA:ARUK-UCL.
DR   GO; GO:0016020; C:membrane; IDA:ARUK-UCL.
DR   GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR   GO; GO:0004175; F:endopeptidase activity; IDA:ARUK-UCL.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0004222; F:metalloendopeptidase activity; IBA:GO_Central.
DR   GO; GO:0016485; P:protein processing; IBA:GO_Central.
DR   GO; GO:0006508; P:proteolysis; IDA:ARUK-UCL.
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:SF141; MEMBRANE METALLO-ENDOPEPTIDASE-LIKE 1; 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.
DR   Genevisible; Q495T6; HS.
PE   2: Evidence at transcript 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..779
FT                   /note="Membrane metallo-endopeptidase-like 1"
FT                   /id="PRO_0000248415"
FT   CHAIN           74..779
FT                   /note="Membrane metallo-endopeptidase-like 1, soluble form"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000248416"
FT   TOPO_DOM        1..27
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        28..48
FT                   /note="Helical; Signal-anchor for type II membrane protein"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        49..779
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          88..779
FT                   /note="Peptidase M13"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT   COILED          515..560
FT                   /evidence="ECO:0000255"
FT   ACT_SITE        614
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01233,
FT                   ECO:0000255|PROSITE-ProRule:PRU10095"
FT   ACT_SITE        680
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT   BINDING         135
FT                   /ligand="a peptide"
FT                   /ligand_id="ChEBI:CHEBI:60466"
FT                   /ligand_note="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         613
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         617
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         676
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT   SITE            73..74
FT                   /note="Cleavage"
FT                   /evidence="ECO:0000250"
FT   CARBOHYD        177
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        207
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        350
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        530
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        657
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        89..94
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT   DISULFID        112..764
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT   DISULFID        120..724
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT   DISULFID        175..439
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT   DISULFID        650..776
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT   VAR_SEQ         159..315
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_020287"
FT   VAR_SEQ         583..611
FT                   /note="VFPAGILQPPFFSKEQPQALNFGGIGMVI -> AYSLSRPWGQYSLPGSSSP
FT                   PSSARSSHRP (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_020288"
FT   VAR_SEQ         612..779
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_020289"
FT   VARIANT         518
FT                   /note="M -> T (in dbSNP:rs3748816)"
FT                   /evidence="ECO:0000269|PubMed:15489334"
FT                   /id="VAR_027348"
FT   CONFLICT        351
FT                   /note="W -> R (in Ref. 4; AAI01029)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        489
FT                   /note="M -> I (in Ref. 4; AAI01031)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   779 AA;  89367 MW;  08C41819F4E81CBD CRC64;
     MGKSEGPVGM VESAGRAGQK RPGFLEGGLL LLLLLVTAAL VALGVLYADR RGKQLPRLAS
     RLCFLQEERT FVKRKPRGIP EAQEVSEVCT TPGCVIAAAR ILQNMDPTTE PCDDFYQFAC
     GGWLRRHVIP ETNSRYSIFD VLRDELEVIL KAVLENSTAK DRPAVEKART LYRSCMNQSV
     IEKRGSQPLL DILEVVGGWP VAMDRWNETV GLEWELERQL ALMNSQFNRR VLIDLFIWND
     DQNSSRHIIY IDQPTLGMPS REYYFNGGSN RKVREAYLQF MVSVATLLRE DANLPRDSCL
     VQEDMVQVLE LETQLAKATV PQEERHDVIA LYHRMGLEEL QSQFGLKGFN WTLFIQTVLS
     SVKIKLLPDE EVVVYGIPYL QNLENIIDTY SARTIQNYLV WRLVLDRIGS LSQRFKDTRV
     NYRKALFGTM VEEVRWRECV GYVNSNMENA VGSLYVREAF PGDSKSMVRE LIDKVRTVFV
     ETLDELGWMD EESKKKAQEK AMSIREQIGH PDYILEEMNR RLDEEYSNLN FSEDLYFENS
     LQNLKVGAQR SLRKLREKVD PNLWIIGAAV VNAFYSPNRN QIVFPAGILQ PPFFSKEQPQ
     ALNFGGIGMV IGHEITHGFD DNGRNFDKNG NMMDWWSNFS TQHFREQSEC MIYQYGNYSW
     DLADEQNVNG FNTLGENIAD NGGVRQAYKA YLKWMAEGGK DQQLPGLDLT HEQLFFINYA
     QVWCGSYRPE FAIQSIKTDV HSPLKYRVLG SLQNLAAFAD TFHCARGTPM HPKERCRVW
//