MMEL1_HUMAN
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 03-AUG-2022, entry version 145.
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. [Q495T6-1]
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 GlyGen; Q495T6; 5 sites.
DR iPTMnet; Q495T6; -.
DR PhosphoSitePlus; Q495T6; -.
DR BioMuta; MMEL1; -.
DR DMDM; 114150028; -.
DR jPOST; Q495T6; -.
DR MassIVE; Q495T6; -.
DR PaxDb; Q495T6; -.
DR PeptideAtlas; Q495T6; -.
DR PRIDE; Q495T6; -.
DR ProteomicsDB; 61971; -. [Q495T6-1]
DR ProteomicsDB; 61972; -. [Q495T6-2]
DR ProteomicsDB; 61973; -. [Q495T6-3]
DR Antibodypedia; 1624; 160 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 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; APRNHDA; -.
DR OrthoDB; 282463at2759; -.
DR PhylomeDB; Q495T6; -.
DR TreeFam; TF315192; -.
DR BRENDA; 3.4.24.B14; 2681.
DR PathwayCommons; Q495T6; -.
DR SignaLink; Q495T6; -.
DR BioGRID-ORCS; 79258; 13 hits in 1070 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 left testis and 89 other tissues.
DR ExpressionAtlas; Q495T6; baseline and differential.
DR Genevisible; Q495T6; HS.
DR GO; GO:0005615; C:extracellular space; IDA:ARUK-UCL.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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:0004222; F:metalloendopeptidase activity; IBA:GO_Central.
DR GO; GO:0008270; F:zinc ion binding; IEA:Ensembl.
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; 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 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
