ID   ASTL_HUMAN              Reviewed;         431 AA.
AC   Q6HA08; Q3KNT0;
DT   27-SEP-2005, integrated into UniProtKB/Swiss-Prot.
DT   11-JAN-2011, sequence version 4.
DT   27-MAR-2024, entry version 134.
DE   RecName: Full=Astacin-like metalloendopeptidase;
DE            EC=3.4.-.-;
DE   AltName: Full=Oocyte astacin;
DE   AltName: Full=Ovastacin;
DE   AltName: Full=ZP2-proteinase {ECO:0000305};
DE   Flags: Precursor;
GN   Name=ASTL {ECO:0000312|HGNC:HGNC:31704};
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 [LARGE SCALE GENOMIC DNA].
RX   PubMed=15815621; DOI=10.1038/nature03466;
RA   Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA   Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA   Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA   Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA   Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA   Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA   Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA   Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA   Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA   McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA   Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA   Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA   Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA   Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA   Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA   Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA   Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA   Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA   Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA   Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA   Wilson R.K.;
RT   "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT   4.";
RL   Nature 434:724-731(2005).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS ARG-222 AND GLN-277.
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   [3]
RP   RETRACTED PAPER.
RX   PubMed=15087446; DOI=10.1074/jbc.m401588200;
RA   Quesada V., Sanchez J., Alvarez J., Lopez-Otin C.;
RT   "Identification and characterization of human and mouse ovastacin, a novel
RT   metalloproteinase similar to hatching enzymes from arthropods, birds,
RT   amphibians, and fish.";
RL   J. Biol. Chem. 279:26627-26634(2004).
RN   [4]
RP   RETRACTION NOTICE OF PUBMED:15087446.
RX   PubMed=30808003; DOI=10.1074/jbc.w118.007326;
RA   Quesada V., Sanchez L.M., Alvarez J., Lopez-Otin C.;
RT   "Withdrawal: Identification and characterization of human and mouse
RT   ovastacin: A novel metalloproteinase similar to hatching enzymes from
RT   arthropods, birds, amphibians, and fish.";
RL   J. Biol. Chem. 294:1432-1432(2019).
RN   [5]
RP   INVOLVEMENT IN OZEMA11.
RX   PubMed=34704130; DOI=10.1007/s00439-021-02388-8;
RA   Maddirevula S., Coskun S., Al-Qahtani M., Aboyousef O., Alhassan S.,
RA   Aldeery M., Alkuraya F.S.;
RT   "ASTL is mutated in female infertility.";
RL   Hum. Genet. 141:49-54(2022).
CC   -!- FUNCTION: Oocyte-specific oolemmal receptor involved in sperm and egg
CC       adhesion and fertilization. Plays a role in the polyspermy inhibition.
CC       Probably acts as a protease for the post-fertilization cleavage of ZP2.
CC       Cleaves the sperm-binding ZP2 at the surface of the zona pellucida
CC       after fertilization and cortical granule exocytosis, rendering the zona
CC       pellucida unable to support further sperm binding.
CC       {ECO:0000250|UniProtKB:Q6HA09}.
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000255|PROSITE-
CC         ProRule:PRU01211};
CC       Note=Binds 1 zinc ion per subunit. {ECO:0000255|PROSITE-
CC       ProRule:PRU01211};
CC   -!- SUBUNIT: Interacts (via N-terminal domain) with SPACA3; the interaction
CC       occurs during fertilization. {ECO:0000250|UniProtKB:Q6HA09}.
CC   -!- INTERACTION:
CC       Q6HA08; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-11998350, EBI-3867333;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q6HA09}. Cell
CC       membrane {ECO:0000250|UniProtKB:Q6HA09}. Cytoplasmic vesicle, secretory
CC       vesicle, Cortical granule {ECO:0000250|UniProtKB:Q6HA09}. Note=Probably
CC       exocytosed from cortical granules during post-fertilization. Detected
CC       throughout the ooplasm of germinal vesicle stage oocytes in early
CC       bilaminar secondary follicles at postnatal (PN) day 3. Detected in the
CC       microvillar domain of the oolemma in arrested ovulated secondary
CC       oocytes and in the first polar body prior to fertilization. Upon
CC       fertilization, detected in the perivitelline space (PVS) and
CC       occasionally on the oolemma in 2-cell through morulae stages.
CC       Colocalizes with SPACA3 at the microvillar domain of the oolemma and in
CC       the perivitelline space (PVS). {ECO:0000250|UniProtKB:Q6HA09}.
CC   -!- DISEASE: Oocyte/zygote/embryo maturation arrest 11 (OZEMA11)
CC       [MIM:619643]: An autosomal recessive disorder characterized by
CC       decreased or absent fertility and poor embryonic outcomes with assisted
CC       reproductive technology. {ECO:0000269|PubMed:34704130}. Note=The
CC       disease may be caused by variants affecting the gene represented in
CC       this entry.
CC   -!- WEB RESOURCE: Name=Protein Spotlight; Note=Life's boundaries - Issue
CC       141 of September2012;
CC       URL="https://web.expasy.org/spotlight/back_issues/141";
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DR   EMBL; AC012307; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC107127; AAI07128.1; -; mRNA.
DR   EMBL; AJ537600; CAD61265.2; -; mRNA.
DR   CCDS; CCDS33249.1; -.
DR   RefSeq; NP_001002036.3; NM_001002036.3.
DR   PDB; 7ST8; X-ray; 2.75 A; S=284-431.
DR   PDBsum; 7ST8; -.
DR   AlphaFoldDB; Q6HA08; -.
DR   SMR; Q6HA08; -.
DR   BioGRID; 136111; 10.
DR   IntAct; Q6HA08; 4.
DR   STRING; 9606.ENSP00000343674; -.
DR   MEROPS; M12.245; -.
DR   iPTMnet; Q6HA08; -.
DR   PhosphoSitePlus; Q6HA08; -.
DR   BioMuta; ASTL; -.
DR   DMDM; 317373556; -.
DR   MassIVE; Q6HA08; -.
DR   PaxDb; 9606-ENSP00000343674; -.
DR   PeptideAtlas; Q6HA08; -.
DR   Antibodypedia; 2745; 121 antibodies from 18 providers.
DR   DNASU; 431705; -.
DR   Ensembl; ENST00000342380.3; ENSP00000343674.2; ENSG00000188886.4.
DR   GeneID; 431705; -.
DR   KEGG; hsa:431705; -.
DR   MANE-Select; ENST00000342380.3; ENSP00000343674.2; NM_001002036.4; NP_001002036.3.
DR   UCSC; uc010yui.2; human.
DR   AGR; HGNC:31704; -.
DR   CTD; 431705; -.
DR   DisGeNET; 431705; -.
DR   GeneCards; ASTL; -.
DR   HGNC; HGNC:31704; ASTL.
DR   HPA; ENSG00000188886; Tissue enhanced (bone).
DR   MalaCards; ASTL; -.
DR   MIM; 608860; gene.
DR   MIM; 619643; phenotype.
DR   neXtProt; NX_Q6HA08; -.
DR   OpenTargets; ENSG00000188886; -.
DR   PharmGKB; PA134922299; -.
DR   VEuPathDB; HostDB:ENSG00000188886; -.
DR   eggNOG; KOG3714; Eukaryota.
DR   GeneTree; ENSGT00940000154856; -.
DR   HOGENOM; CLU_640213_0_0_1; -.
DR   InParanoid; Q6HA08; -.
DR   OMA; KWPTGGG; -.
DR   OrthoDB; 2876645at2759; -.
DR   PhylomeDB; Q6HA08; -.
DR   TreeFam; TF315280; -.
DR   BRENDA; 3.4.24.21; 2681.
DR   PathwayCommons; Q6HA08; -.
DR   SignaLink; Q6HA08; -.
DR   BioGRID-ORCS; 431705; 17 hits in 1144 CRISPR screens.
DR   GenomeRNAi; 431705; -.
DR   Pharos; Q6HA08; Tbio.
DR   PRO; PR:Q6HA08; -.
DR   Proteomes; UP000005640; Chromosome 2.
DR   RNAct; Q6HA08; Protein.
DR   Bgee; ENSG00000188886; Expressed in bone marrow and 76 other cell types or tissues.
DR   GO; GO:0060473; C:cortical granule; ISS:UniProtKB.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR   GO; GO:0070001; F:aspartic-type peptidase activity; ISS:UniProtKB.
DR   GO; GO:0070002; F:glutamic-type peptidase activity; ISS:UniProtKB.
DR   GO; GO:0004222; F:metalloendopeptidase activity; IBA:GO_Central.
DR   GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR   GO; GO:0007155; P:cell adhesion; ISS:UniProtKB.
DR   GO; GO:0009566; P:fertilization; ISS:UniProtKB.
DR   GO; GO:2000360; P:negative regulation of binding of sperm to zona pellucida; ISS:UniProtKB.
DR   GO; GO:0010954; P:positive regulation of protein processing; ISS:UniProtKB.
DR   GO; GO:0060468; P:prevention of polyspermy; ISS:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   Gene3D; 3.40.390.10; Collagenase (Catalytic Domain); 1.
DR   InterPro; IPR024079; MetalloPept_cat_dom_sf.
DR   InterPro; IPR001506; Peptidase_M12A.
DR   InterPro; IPR006026; Peptidase_Metallo.
DR   PANTHER; PTHR10127:SF887; ASTACIN-LIKE METALLOENDOPEPTIDASE; 1.
DR   PANTHER; PTHR10127; DISCOIDIN, CUB, EGF, LAMININ , AND ZINC METALLOPROTEASE DOMAIN CONTAINING; 1.
DR   Pfam; PF01400; Astacin; 1.
DR   PRINTS; PR00480; ASTACIN.
DR   SMART; SM00235; ZnMc; 1.
DR   SUPFAM; SSF55486; Metalloproteases ('zincins'), catalytic domain; 1.
DR   PROSITE; PS51864; ASTACIN; 1.
DR   PROSITE; PS00142; ZINC_PROTEASE; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Cell membrane; Cytoplasm; Cytoplasmic vesicle;
KW   Disulfide bond; Fertilization; Hydrolase; Membrane; Metal-binding;
KW   Metalloprotease; Protease; Reference proteome; Signal; Zinc; Zymogen.
FT   SIGNAL          1..23
FT                   /evidence="ECO:0000255"
FT   CHAIN           24..431
FT                   /note="Astacin-like metalloendopeptidase"
FT                   /evidence="ECO:0000255"
FT                   /id="PRO_0000041964"
FT   DOMAIN          85..282
FT                   /note="Peptidase M12A"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT   REGION          283..304
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          317..431
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        386..406
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        183
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT   BINDING         182
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT   BINDING         186
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT   BINDING         192
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT   DISULFID        132..281
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT   DISULFID        153..172
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT   VARIANT         204
FT                   /note="R -> H (in dbSNP:rs41320144)"
FT                   /id="VAR_061734"
FT   VARIANT         222
FT                   /note="Q -> R (in dbSNP:rs749458)"
FT                   /evidence="ECO:0000269|PubMed:15489334"
FT                   /id="VAR_033491"
FT   VARIANT         277
FT                   /note="K -> Q (in dbSNP:rs1657502)"
FT                   /evidence="ECO:0000269|PubMed:15489334"
FT                   /id="VAR_057063"
FT   HELIX           309..316
FT                   /evidence="ECO:0007829|PDB:7ST8"
SQ   SEQUENCE   431 AA;  45936 MW;  6E1FD4653506AFC1 CRC64;
     MEGVGGLWPW VLGLLSLPGV ILGAPLASSC AGACGTSFPD GLTPEGTQAS GDKDIPAINQ
     GLILEETPES SFLIEGDIIR PSPFRLLSAT SNKWPMGGSG VVEVPFLLSS KYDEPSRQVI
     LEALAEFERS TCIRFVTYQD QRDFISIIPM YGCFSSVGRS GGMQVVSLAP TCLQKGRGIV
     LHELMHVLGF WHEHTRADRD RYIRVNWNEI LPGFEINFIK SQSSNMLTPY DYSSVMHYGR
     LAFSRRGLPT ITPLWAPSVH IGQRWNLSAS DITRVLKLYG CSPSGPRPRG RGSHAHSTGR
     SPAPASLSLQ RLLEALSAES RSPDPSGSSA GGQPVPAGPG ESPHGWESPA LKKLSAEASA
     RQPQTLASSP RSRPGAGAPG VAQEQSWLAG VSTKPTVPSS EAGIQPVPVQ GSPALPGGCV
     PRNHFKGMSE D
//