ID   ADA21_HUMAN             Reviewed;         722 AA.
AC   Q9UKJ8; O43507; Q2VPC6; Q32MR0;
DT   01-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT   18-MAY-2010, sequence version 2.
DT   27-MAR-2024, entry version 197.
DE   RecName: Full=Disintegrin and metalloproteinase domain-containing protein 21;
DE            Short=ADAM 21;
DE            EC=3.4.24.-;
DE   Flags: Precursor;
GN   Name=ADAM21;
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 [GENOMIC DNA].
RX   PubMed=10524237; DOI=10.1016/s0378-1119(99)00302-9;
RA   Poindexter K., Nelson N., DuBose R.F., Black R.A., Cerretti D.P.;
RT   "The identification of seven metalloproteinase-disintegrin (ADAM) genes
RT   from genomic libraries.";
RL   Gene 237:61-70(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12508121; DOI=10.1038/nature01348;
RA   Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA   Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA   Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA   Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA   Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA   Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA   Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA   Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA   Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA   Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA   Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA   Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA   Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA   Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA   Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA   Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA   Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA   Waterston R., Hood L., Weissenbach J.;
RT   "The DNA sequence and analysis of human chromosome 14.";
RL   Nature 421:601-607(2003).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 181-722.
RC   TISSUE=Testis;
RX   PubMed=9469942; DOI=10.1016/s0378-1119(97)00597-0;
RA   Hooft van Huijsduijnen R.;
RT   "ADAM 20 and 21; two novel human testis-specific membrane metalloproteases
RT   with similarity to fertilin-alpha.";
RL   Gene 206:273-282(1998).
CC   -!- FUNCTION: May be involved in sperm maturation and/or fertilization. May
CC       also be involved in epithelia functions associated with establishing
CC       and maintaining gradients of ions or nutrients.
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000305};
CC       Note=Binds 1 zinc ion per subunit. {ECO:0000305};
CC   -!- INTERACTION:
CC       Q9UKJ8; P34972: CNR2; NbExp=3; IntAct=EBI-12046857, EBI-2835940;
CC       Q9UKJ8; O43765: SGTA; NbExp=3; IntAct=EBI-12046857, EBI-347996;
CC   -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane protein.
CC   -!- DOMAIN: A tripeptide motif (VGE) within disintegrin-like domain could
CC       be involved in the binding to egg integrin receptor and thus could
CC       mediate sperm/egg binding.
CC   -!- DOMAIN: The cysteine-rich domain encodes putative cell-fusion peptides,
CC       which could be involved in sperm-egg fusion.
CC   -!- DOMAIN: The conserved cysteine present in the cysteine-switch motif
CC       binds the catalytic zinc ion, thus inhibiting the enzyme. The
CC       dissociation of the cysteine from the zinc ion upon the activation-
CC       peptide release activates the enzyme.
CC   -!- PTM: Has no obvious cleavage site for furin endopeptidase, suggesting
CC       that the proteolytic processing is regulated.
CC   -!- MISCELLANEOUS: May be the functional equivalent of ADAM 1/fertilin
CC       alpha which is a pseudogene in human.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; AF158644; AAD55255.1; -; Genomic_DNA.
DR   EMBL; AL357153; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL391223; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC109024; AAI09025.1; -; mRNA.
DR   EMBL; BC109025; AAI09026.1; -; mRNA.
DR   EMBL; AF029900; AAC52042.1; -; mRNA.
DR   CCDS; CCDS9804.1; -.
DR   RefSeq; NP_003804.2; NM_003813.3.
DR   AlphaFoldDB; Q9UKJ8; -.
DR   SMR; Q9UKJ8; -.
DR   BioGRID; 114283; 113.
DR   IntAct; Q9UKJ8; 28.
DR   STRING; 9606.ENSP00000474385; -.
DR   MEROPS; M12.234; -.
DR   GlyCosmos; Q9UKJ8; 7 sites, No reported glycans.
DR   GlyGen; Q9UKJ8; 7 sites.
DR   iPTMnet; Q9UKJ8; -.
DR   PhosphoSitePlus; Q9UKJ8; -.
DR   BioMuta; ADAM21; -.
DR   DMDM; 296434388; -.
DR   MassIVE; Q9UKJ8; -.
DR   PaxDb; 9606-ENSP00000474385; -.
DR   PeptideAtlas; Q9UKJ8; -.
DR   ProteomicsDB; 84810; -.
DR   Antibodypedia; 25130; 42 antibodies from 17 providers.
DR   DNASU; 8747; -.
DR   Ensembl; ENST00000603540.2; ENSP00000474385.1; ENSG00000139985.8.
DR   Ensembl; ENST00000679631.1; ENSP00000506213.1; ENSG00000139985.8.
DR   GeneID; 8747; -.
DR   KEGG; hsa:8747; -.
DR   MANE-Select; ENST00000603540.2; ENSP00000474385.1; NM_003813.4; NP_003804.2.
DR   UCSC; uc001xmd.4; human.
DR   AGR; HGNC:200; -.
DR   CTD; 8747; -.
DR   DisGeNET; 8747; -.
DR   GeneCards; ADAM21; -.
DR   HGNC; HGNC:200; ADAM21.
DR   HPA; ENSG00000139985; Tissue enriched (testis).
DR   MIM; 603713; gene.
DR   neXtProt; NX_Q9UKJ8; -.
DR   OpenTargets; ENSG00000139985; -.
DR   PharmGKB; PA24517; -.
DR   VEuPathDB; HostDB:ENSG00000139985; -.
DR   eggNOG; KOG3607; Eukaryota.
DR   GeneTree; ENSGT00940000162712; -.
DR   HOGENOM; CLU_012714_4_0_1; -.
DR   InParanoid; Q9UKJ8; -.
DR   OMA; WWTHSWF; -.
DR   OrthoDB; 5406290at2759; -.
DR   PhylomeDB; Q9UKJ8; -.
DR   TreeFam; TF314733; -.
DR   PathwayCommons; Q9UKJ8; -.
DR   Reactome; R-HSA-2534343; Interaction With Cumulus Cells And The Zona Pellucida.
DR   SignaLink; Q9UKJ8; -.
DR   BioGRID-ORCS; 8747; 34 hits in 1114 CRISPR screens.
DR   GenomeRNAi; 8747; -.
DR   Pharos; Q9UKJ8; Tdark.
DR   PRO; PR:Q9UKJ8; -.
DR   Proteomes; UP000005640; Chromosome 14.
DR   RNAct; Q9UKJ8; Protein.
DR   Bgee; ENSG00000139985; Expressed in sperm and 81 other cell types or tissues.
DR   GO; GO:0030424; C:axon; IEA:Ensembl.
DR   GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central.
DR   GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR   GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR   GO; GO:1990913; C:sperm head 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; TAS:ProtInc.
DR   GO; GO:0008584; P:male gonad development; IBA:GO_Central.
DR   GO; GO:0006508; P:proteolysis; IBA:GO_Central.
DR   GO; GO:0007338; P:single fertilization; TAS:ProtInc.
DR   CDD; cd04269; ZnMc_adamalysin_II_like; 1.
DR   Gene3D; 3.40.390.10; Collagenase (Catalytic Domain); 1.
DR   Gene3D; 4.10.70.10; Disintegrin domain; 1.
DR   InterPro; IPR006586; ADAM_Cys-rich.
DR   InterPro; IPR018358; Disintegrin_CS.
DR   InterPro; IPR001762; Disintegrin_dom.
DR   InterPro; IPR036436; Disintegrin_dom_sf.
DR   InterPro; IPR000742; EGF-like_dom.
DR   InterPro; IPR024079; MetalloPept_cat_dom_sf.
DR   InterPro; IPR001590; Peptidase_M12B.
DR   InterPro; IPR002870; Peptidase_M12B_N.
DR   InterPro; IPR034027; Reprolysin_adamalysin.
DR   PANTHER; PTHR11905; ADAM A DISINTEGRIN AND METALLOPROTEASE DOMAIN; 1.
DR   PANTHER; PTHR11905:SF116; DISINTEGRIN AND METALLOPROTEINASE DOMAIN-CONTAINING PROTEIN 21; 1.
DR   Pfam; PF08516; ADAM_CR; 1.
DR   Pfam; PF00200; Disintegrin; 1.
DR   Pfam; PF01562; Pep_M12B_propep; 1.
DR   Pfam; PF01421; Reprolysin; 1.
DR   PRINTS; PR00289; DISINTEGRIN.
DR   SMART; SM00608; ACR; 1.
DR   SMART; SM00050; DISIN; 1.
DR   SUPFAM; SSF57552; Blood coagulation inhibitor (disintegrin); 1.
DR   SUPFAM; SSF55486; Metalloproteases ('zincins'), catalytic domain; 1.
DR   PROSITE; PS50215; ADAM_MEPRO; 1.
DR   PROSITE; PS00427; DISINTEGRIN_1; 1.
DR   PROSITE; PS50214; DISINTEGRIN_2; 1.
DR   PROSITE; PS01186; EGF_2; 1.
DR   PROSITE; PS00142; ZINC_PROTEASE; 1.
DR   Genevisible; Q9UKJ8; HS.
PE   1: Evidence at protein level;
KW   Disulfide bond; EGF-like domain; Glycoprotein; Hydrolase; Membrane;
KW   Metal-binding; Metalloprotease; Protease; Reference proteome; Signal;
KW   Transmembrane; Transmembrane helix; Zinc; Zymogen.
FT   SIGNAL          1..31
FT                   /evidence="ECO:0000255"
FT   PROPEP          32..196
FT                   /evidence="ECO:0000255"
FT                   /id="PRO_0000029108"
FT   CHAIN           197..722
FT                   /note="Disintegrin and metalloproteinase domain-containing
FT                   protein 21"
FT                   /id="PRO_0000029109"
FT   TOPO_DOM        197..681
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        682..702
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        703..722
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          208..398
FT                   /note="Peptidase M12B"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00276"
FT   DOMAIN          406..492
FT                   /note="Disintegrin"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00068"
FT   DOMAIN          634..663
FT                   /note="EGF-like"
FT   MOTIF           171..178
FT                   /note="Cysteine switch"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        342
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00276,
FT                   ECO:0000255|PROSITE-ProRule:PRU10095"
FT   BINDING         173
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /note="in inhibited form"
FT                   /evidence="ECO:0000250"
FT   BINDING         341
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255"
FT   BINDING         345
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255"
FT   BINDING         351
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        164
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        227
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        377
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        437
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        478
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        546
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        600
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        316..393
FT                   /evidence="ECO:0000250"
FT   DISULFID        356..378
FT                   /evidence="ECO:0000250"
FT   DISULFID        358..363
FT                   /evidence="ECO:0000250"
FT   DISULFID        464..484
FT                   /evidence="ECO:0000250"
FT   DISULFID        634..645
FT                   /evidence="ECO:0000250"
FT   DISULFID        639..651
FT                   /evidence="ECO:0000250"
FT   DISULFID        653..662
FT                   /evidence="ECO:0000250"
FT   CONFLICT        95
FT                   /note="D -> E (in Ref. 1; AAD55255 and 3;
FT                   AAI09025/AAI09026)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        117
FT                   /note="A -> G (in Ref. 1; AAD55255 and 3;
FT                   AAI09025/AAI09026)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        161
FT                   /note="I -> V (in Ref. 1; AAD55255 and 3;
FT                   AAI09025/AAI09026)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        181
FT                   /note="A -> G (in Ref. 3; AAC52042)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        247
FT                   /note="K -> Q (in Ref. 1; AAD55255 and 3;
FT                   AAI09025/AAI09026)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        345
FT                   /note="H -> Y (in Ref. 3; AAC52042)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   722 AA;  80834 MW;  4D18503812A6C02F CRC64;
     MAVDGTLVYI RVTLLLLWLG VFLSISGYCQ AGPSQHFTSP EVVIPLKVIS RGRSAKAPGW
     LSYSLRFGGQ KHVVHMRVKK LLVSRHLPVF TYTDDRALLE DQLFIPDDCY YHGYVEAAPE
     SLVVFSACFG GFRGVLKISG LTYEIEPIRH SATFEHLVYK INSNETQFPA MRCGLTEKEV
     ARQQLEFEEA ENSALEPKSA GDWWTHAWFL ELVVVVNHDF FIYSQSNISK VQEDVFLVVN
     IVDSMYKQLG TYIILIGIEI WNQGNVFPMT SIEQVLNDFS QWKQISLSQL QHDAAHMFIK
     NSLISILGLA YVAGICRPPI DCGVDNFQGD TWSLFANTVA HELGHTLGMQ HDEEFCFCGE
     RGCIMNTFRV PAEKFTNCSY ADFMKTTLNQ GSCLHNPPRL GEIFMLKRCG NGVVEREEQC
     DCGSVQQCEQ DACCLLNCTL RPGAACAFGL CCKDCKFMPS GELCRQEVNE CDLPEWCNGT
     SHQCPEDRYV QDGIPCSDSA YCYQKRCNNH DQHCREIFGK DAKSASQNCY KEINSQGNRF
     GHCGINGTTY LKCHISDVFC GRVQCENVRD IPLLQDHFTL QHTHINGVTC WGIDYHLRMN
     ISDIGEVKDG TVCGPGKICI HKKCVSLSVL SHVCLPETCN MKGICNNKHH CHCGYGWSPP
     YCQHRGYGGS IDSGPASAKR GVFLPLIVIP SLSVLTFLFT VGLLMYLRQC SGPKETKAHS
     SG
//