MMP21_HUMAN
ID MMP21_HUMAN Reviewed; 569 AA.
AC Q8N119; Q5VZP9; Q8NG02;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 11-JAN-2011, sequence version 2.
DT 03-AUG-2022, entry version 160.
DE RecName: Full=Matrix metalloproteinase-21;
DE Short=MMP-21;
DE EC=3.4.24.-;
DE Flags: Precursor;
GN Name=MMP21;
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], AND TISSUE SPECIFICITY.
RX PubMed=12490321; DOI=10.1016/s0378-1119(02)01088-0;
RA Ahokas K., Lohi J., Lohi H., Elomaa O., Karjalainen-Lindsberg M.-L.,
RA Kere J., Saarialho-Kere U.;
RT "Matrix metalloproteinase-21, the human orthologue for XMMP, is expressed
RT during fetal development and in cancer.";
RL Gene 301:31-41(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], FUNCTION, TISSUE SPECIFICITY, AND
RP VARIANT ALA-191.
RC TISSUE=Kidney;
RX PubMed=12617721; DOI=10.1042/bj20030174;
RA Marchenko G.N., Marchenko N.D., Strongin A.Y.;
RT "The structure and regulation of the human and mouse matrix
RT metalloproteinase-21 gene and protein.";
RL Biochem. J. 372:503-515(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLU-95; GLN-115; ALA-191;
RP GLY-349 AND VAL-454.
RG NIEHS SNPs program;
RL Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [5]
RP INVOLVEMENT IN HTX7, AND FUNCTION.
RX PubMed=26429889; DOI=10.1136/jmedgenet-2015-103336;
RA Perles Z., Moon S., Ta-Shma A., Yaacov B., Francescatto L., Edvardson S.,
RA Rein A.J., Elpeleg O., Katsanis N.;
RT "A human laterality disorder caused by a homozygous deleterious mutation in
RT MMP21.";
RL J. Med. Genet. 52:840-847(2015).
RN [6]
RP INVOLVEMENT IN HTX7, VARIANTS HTX7 TRP-31; LYS-215; THR-226; PRO-321;
RP CYS-360; HIS-375 AND GLY-408, AND FUNCTION.
RX PubMed=26437028; DOI=10.1038/ng.3376;
RA Guimier A., Gabriel G.C., Bajolle F., Tsang M., Liu H., Noll A.,
RA Schwartz M., El Malti R., Smith L.D., Klena N.T., Jimenez G., Miller N.A.,
RA Oufadem M., Moreau de Bellaing A., Yagi H., Saunders C.J., Baker C.N.,
RA Di Filippo S., Peterson K.A., Thiffault I., Bole-Feysot C., Cooley L.D.,
RA Farrow E.G., Masson C., Schoen P., Deleuze J.F., Nitschke P., Lyonnet S.,
RA de Pontual L., Murray S.A., Bonnet D., Kingsmore S.F., Amiel J.,
RA Bouvagnet P., Lo C.W., Gordon C.T.;
RT "MMP21 is mutated in human heterotaxy and is required for normal left-right
RT asymmetry in vertebrates.";
RL Nat. Genet. 47:1260-1263(2015).
RN [7]
RP INVOLVEMENT IN HTX7, VARIANTS HTX7 TYR-283 AND THR-285, AND FUNCTION.
RX PubMed=26437029; DOI=10.1038/ng.3410;
RG DDD study;
RA Akawi N., McRae J., Ansari M., Balasubramanian M., Blyth M., Brady A.F.,
RA Clayton S., Cole T., Deshpande C., Fitzgerald T.W., Foulds N., Francis R.,
RA Gabriel G., Gerety S.S., Goodship J., Hobson E., Jones W.D., Joss S.,
RA King D., Klena N., Kumar A., Lees M., Lelliott C., Lord J., McMullan D.,
RA O'Regan M., Osio D., Piombo V., Prigmore E., Rajan D., Rosser E.,
RA Sifrim A., Smith A., Swaminathan G.J., Turnpenny P., Whitworth J.,
RA Wright C.F., Firth H.V., Barrett J.C., Lo C.W., FitzPatrick D.R.,
RA Hurles M.E.;
RT "Discovery of four recessive developmental disorders using probabilistic
RT genotype and phenotype matching among 4,125 families.";
RL Nat. Genet. 47:1363-1369(2015).
CC -!- FUNCTION: Plays a specialized role in the generation of left-right
CC asymmetry during embryogenesis. May act as a negative regulator of the
CC NOTCH-signaling pathway (PubMed:26429889, PubMed:26437028). Cleaves
CC alpha-1-antitrypsin (PubMed:12617721). {ECO:0000269|PubMed:12617721,
CC ECO:0000269|PubMed:26429889, ECO:0000269|PubMed:26437028}.
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000250};
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Identified in fetal brain, kidney and liver. In
CC adult tissues found primarily in ovary, kidney, liver, lung, placenta,
CC brain and peripheral blood leukocytes. Expressed as well in various
CC cancer cell lines. {ECO:0000269|PubMed:12490321,
CC ECO:0000269|PubMed:12617721}.
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: The precursor is cleaved by a furin endopeptidase. {ECO:0000250}.
CC -!- DISEASE: Heterotaxy, visceral, 7, autosomal (HTX7) [MIM:616749]: A form
CC of visceral heterotaxy, a complex disorder due to disruption of the
CC normal left-right asymmetry of the thoracoabdominal organs. Visceral
CC heterotaxy or situs ambiguus results in randomization of the placement
CC of visceral organs, including the heart, lungs, liver, spleen, and
CC stomach. The organs are oriented randomly with respect to the left-
CC right axis and with respect to one another. It can be associated with a
CC variety of congenital defects including cardiac malformations. HTX7
CC inheritance is autosomal recessive. {ECO:0000269|PubMed:26429889,
CC ECO:0000269|PubMed:26437028, ECO:0000269|PubMed:26437029}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the peptidase M10A family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/mmp21/";
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DR EMBL; AF331526; AAM92903.1; -; mRNA.
DR EMBL; AY121358; AAM78033.1; -; Genomic_DNA.
DR EMBL; AF520613; AAM75352.1; -; mRNA.
DR EMBL; AY885252; AAW62254.1; -; Genomic_DNA.
DR EMBL; AL158835; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL360176; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS7647.1; -.
DR RefSeq; NP_671724.1; NM_147191.1.
DR AlphaFoldDB; Q8N119; -.
DR SMR; Q8N119; -.
DR BioGRID; 125624; 1.
DR STRING; 9606.ENSP00000357798; -.
DR DrugBank; DB00786; Marimastat.
DR MEROPS; M10.026; -.
DR GlyGen; Q8N119; 1 site.
DR iPTMnet; Q8N119; -.
DR PhosphoSitePlus; Q8N119; -.
DR BioMuta; MMP21; -.
DR DMDM; 317373390; -.
DR PaxDb; Q8N119; -.
DR PeptideAtlas; Q8N119; -.
DR PRIDE; Q8N119; -.
DR Antibodypedia; 19175; 97 antibodies from 25 providers.
DR DNASU; 118856; -.
DR Ensembl; ENST00000368808.3; ENSP00000357798.3; ENSG00000154485.5.
DR GeneID; 118856; -.
DR KEGG; hsa:118856; -.
DR MANE-Select; ENST00000368808.3; ENSP00000357798.3; NM_147191.1; NP_671724.1.
DR UCSC; uc001liu.5; human.
DR CTD; 118856; -.
DR DisGeNET; 118856; -.
DR GeneCards; MMP21; -.
DR HGNC; HGNC:14357; MMP21.
DR HPA; ENSG00000154485; Tissue enriched (epididymis).
DR MalaCards; MMP21; -.
DR MIM; 608416; gene.
DR MIM; 616749; phenotype.
DR neXtProt; NX_Q8N119; -.
DR OpenTargets; ENSG00000154485; -.
DR Orphanet; 157769; Situs ambiguus.
DR Orphanet; 101063; Situs inversus totalis.
DR PharmGKB; PA134885721; -.
DR VEuPathDB; HostDB:ENSG00000154485; -.
DR eggNOG; KOG1565; Eukaryota.
DR GeneTree; ENSGT00940000159140; -.
DR HOGENOM; CLU_015489_9_0_1; -.
DR InParanoid; Q8N119; -.
DR OMA; CWLAAPW; -.
DR OrthoDB; 1075463at2759; -.
DR PhylomeDB; Q8N119; -.
DR TreeFam; TF315428; -.
DR PathwayCommons; Q8N119; -.
DR BioGRID-ORCS; 118856; 10 hits in 1069 CRISPR screens.
DR GeneWiki; MMP21; -.
DR GenomeRNAi; 118856; -.
DR Pharos; Q8N119; Tbio.
DR PRO; PR:Q8N119; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; Q8N119; protein.
DR Bgee; ENSG00000154485; Expressed in corpus epididymis and 95 other tissues.
DR ExpressionAtlas; Q8N119; baseline and differential.
DR Genevisible; Q8N119; HS.
DR GO; GO:0031012; C:extracellular matrix; IEA:InterPro.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0004222; F:metalloendopeptidase activity; IBA:GO_Central.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0030574; P:collagen catabolic process; IBA:GO_Central.
DR GO; GO:0060976; P:coronary vasculature development; IEA:Ensembl.
DR GO; GO:0061371; P:determination of heart left/right asymmetry; ISS:UniProtKB.
DR GO; GO:0007368; P:determination of left/right symmetry; IMP:UniProtKB.
DR GO; GO:0030198; P:extracellular matrix organization; IBA:GO_Central.
DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR CDD; cd00094; HX; 1.
DR CDD; cd04278; ZnMc_MMP; 1.
DR Gene3D; 2.110.10.10; -; 2.
DR Gene3D; 3.40.390.10; -; 1.
DR InterPro; IPR000585; Hemopexin-like_dom.
DR InterPro; IPR036375; Hemopexin-like_dom_sf.
DR InterPro; IPR018487; Hemopexin-like_repeat.
DR InterPro; IPR033739; M10A_MMP.
DR InterPro; IPR024079; MetalloPept_cat_dom_sf.
DR InterPro; IPR001818; Pept_M10_metallopeptidase.
DR InterPro; IPR021190; Pept_M10A.
DR InterPro; IPR006026; Peptidase_Metallo.
DR InterPro; IPR002477; Peptidoglycan-bd-like.
DR InterPro; IPR036365; PGBD-like_sf.
DR Pfam; PF00045; Hemopexin; 3.
DR Pfam; PF00413; Peptidase_M10; 1.
DR Pfam; PF01471; PG_binding_1; 1.
DR PIRSF; PIRSF001191; Peptidase_M10A_matrix; 1.
DR PRINTS; PR00138; MATRIXIN.
DR SMART; SM00120; HX; 4.
DR SMART; SM00235; ZnMc; 1.
DR SUPFAM; SSF47090; SSF47090; 1.
DR SUPFAM; SSF50923; SSF50923; 1.
DR PROSITE; PS51642; HEMOPEXIN_2; 4.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 2: Evidence at transcript level;
KW Calcium; Cleavage on pair of basic residues; Disulfide bond; Glycoprotein;
KW Heterotaxy; Hydrolase; Metal-binding; Metalloprotease; Protease;
KW Reference proteome; Repeat; Secreted; Signal; Zinc; Zymogen.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT PROPEP 25..144
FT /evidence="ECO:0000250"
FT /id="PRO_0000028839"
FT CHAIN 145..569
FT /note="Matrix metalloproteinase-21"
FT /id="PRO_0000028840"
FT REPEAT 330..389
FT /note="Hemopexin 1"
FT REPEAT 391..447
FT /note="Hemopexin 2"
FT REPEAT 448..496
FT /note="Hemopexin 3"
FT REPEAT 503..559
FT /note="Hemopexin 4"
FT REGION 115..166
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 115..122
FT /note="Cysteine switch"
FT /evidence="ECO:0000250"
FT COMPBIAS 119..143
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 284
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 117
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 283
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 287
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 293
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT CARBOHYD 372
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 329..560
FT /evidence="ECO:0000250"
FT VARIANT 31
FT /note="R -> W (in HTX7; found associated with K-215;
FT dbSNP:rs746379956)"
FT /evidence="ECO:0000269|PubMed:26437028"
FT /id="VAR_076319"
FT VARIANT 95
FT /note="A -> E (in dbSNP:rs28381282)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_022291"
FT VARIANT 115
FT /note="P -> Q (in dbSNP:rs28381284)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_022292"
FT VARIANT 191
FT /note="V -> A (in dbSNP:rs10901425)"
FT /evidence="ECO:0000269|PubMed:12617721, ECO:0000269|Ref.3"
FT /id="VAR_019393"
FT VARIANT 215
FT /note="E -> K (in HTX7; found associated with W-31;
FT dbSNP:rs145789868)"
FT /evidence="ECO:0000269|PubMed:26437028"
FT /id="VAR_076320"
FT VARIANT 226
FT /note="I -> T (in HTX7; dbSNP:rs781127723)"
FT /evidence="ECO:0000269|PubMed:26437028"
FT /id="VAR_076321"
FT VARIANT 263
FT /note="D -> E (in dbSNP:rs34811493)"
FT /id="VAR_032824"
FT VARIANT 283
FT /note="H -> Y (in HTX7; dbSNP:rs1434829861)"
FT /evidence="ECO:0000269|PubMed:26437029"
FT /id="VAR_076322"
FT VARIANT 285
FT /note="I -> T (in HTX7; dbSNP:rs747668147)"
FT /evidence="ECO:0000269|PubMed:26437029"
FT /id="VAR_076323"
FT VARIANT 311
FT /note="A -> T (in dbSNP:rs17173746)"
FT /id="VAR_057803"
FT VARIANT 321
FT /note="A -> P (in HTX7; dbSNP:rs773125891)"
FT /evidence="ECO:0000269|PubMed:26437028"
FT /id="VAR_076324"
FT VARIANT 349
FT /note="E -> G (in dbSNP:rs28381302)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_022293"
FT VARIANT 360
FT /note="R -> C (in HTX7; dbSNP:rs946722250)"
FT /evidence="ECO:0000269|PubMed:26437028"
FT /id="VAR_076325"
FT VARIANT 360
FT /note="R -> H (in dbSNP:rs17153524)"
FT /id="VAR_057804"
FT VARIANT 375
FT /note="R -> H (in HTX7)"
FT /evidence="ECO:0000269|PubMed:26437028"
FT /id="VAR_076326"
FT VARIANT 408
FT /note="R -> G (in HTX7; unknown pathological significance;
FT dbSNP:rs150320323)"
FT /evidence="ECO:0000269|PubMed:26437028"
FT /id="VAR_076327"
FT VARIANT 454
FT /note="A -> V (in dbSNP:rs28381319)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_022294"
SQ SEQUENCE 569 AA; 65043 MW; 6785EF34F5B5105E CRC64;
MLAASIFRPT LLLCWLAAPW PTQPESLFHS RDRSDLEPSP LRQAKPIADL HAAQRFLSRY
GWSGVWAAWG PSPEGPPETP KGAALAEAVR RFQRANALPA SGELDAATLA AMNRPRCGVP
DMRPPPPSAP PSPPGPPPRA RSRRSPRAPL SLSRRGWQPR GYPDGGAAQA FSKRTLSWRL
LGEALSSQLS VADQRRIVAL AFRMWSEVTP LDFREDLAAP GAAVDIKLGF GRGRHLGCPR
AFDGSGQEFA HAWRLGDIHF DDDEHFTPPT SDTGISLLKV AVHEIGHVLG LPHTYRTGSI
MQPNYIPQEP AFELDWSDRK AIQKLYGSCE GSFDTAFDWI RKERNQYGEV MVRFSTYFFR
NSWYWLYENR NNRTRYGDPI QILTGWPGIP THNIDAFVHI WTWKRDERYF FQGNQYWRYD
SDKDQALTED EQGKSYPKLI SEGFPGIPSP LDTAFYDRRQ KLIYFFKESL VFAFDVNRNR
VLNSYPKRIT EVFPAVIPQN HPFRNIDSAY YSYAYNSIFF FKGNAYWKVV NDKDKQQNSW
LPANGLFPKK FISEKWFDVC DVHISTLNM
