ID TLL2_HUMAN Reviewed; 1015 AA.
AC Q9Y6L7; A6NDK0; Q2M1H1; Q6PJN5; Q9UQ00;
DT 07-FEB-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 27-MAR-2024, entry version 180.
DE RecName: Full=Tolloid-like protein 2;
DE EC=3.4.24.-;
DE Flags: Precursor;
GN Name=TLL2; Synonyms=KIAA0932;
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 PROTEIN SEQUENCE OF 150-154.
RC TISSUE=Placenta;
RX PubMed=10479448; DOI=10.1006/dbio.1999.9383;
RA Scott I.C., Blitz I.L., Pappano W.N., Imamura Y., Clark T.G.,
RA Steiglitz B.M., Thomas C.L., Maas S.A., Takahara K., Cho K.W.,
RA Greenspan D.S.;
RT "Mammalian BMP-1/Tolloid-related metalloproteinases, including novel family
RT member mammalian Tolloid-like 2, have differential enzymatic activities and
RT distributions of expression relevant to patterning and skeletogenesis.";
RL Dev. Biol. 213:283-300(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=10231032; DOI=10.1093/dnares/6.1.63;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XIII. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 6:63-70(1999).
RN [3]
RP SEQUENCE REVISION.
RA Ohara O., Nagase T., Kikuno R.;
RL Submitted (FEB-1999) 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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Ovary;
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 [6]
RP CHARACTERIZATION.
RX PubMed=11313359; DOI=10.1074/jbc.m102352200;
RA Uzel M.I., Scott I.C., Babakhanlou-Chase H., Palamakumbura A.H.,
RA Pappano W.N., Hong H.-H., Greenspan D.S., Trackman P.C.;
RT "Multiple bone morphogenetic protein 1-related mammalian metalloproteinases
RT process pro-lysyl oxidase at the correct physiological site and control
RT lysyl oxidase activation in mouse embryo fibroblast cultures.";
RL J. Biol. Chem. 276:22537-22543(2001).
CC -!- FUNCTION: Protease which specifically processes pro-lysyl oxidase.
CC Required for the embryonic development. Predominant protease, which in
CC the development, influences dorsal-ventral patterning and
CC skeletogenesis.
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU01211};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000255|PROSITE-
CC ProRule:PRU01211};
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA76776.2; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AF059516; AAD42979.1; -; mRNA.
DR EMBL; AB023149; BAA76776.2; ALT_INIT; mRNA.
DR EMBL; AL138765; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL136181; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL391136; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC013871; AAH13871.1; -; mRNA.
DR EMBL; BC112341; AAI12342.1; -; mRNA.
DR EMBL; BC112366; AAI12367.1; -; mRNA.
DR EMBL; BC113577; AAI13578.1; -; mRNA.
DR CCDS; CCDS7449.1; -.
DR RefSeq; NP_036597.1; NM_012465.3.
DR AlphaFoldDB; Q9Y6L7; -.
DR SMR; Q9Y6L7; -.
DR BioGRID; 112948; 29.
DR IntAct; Q9Y6L7; 1.
DR STRING; 9606.ENSP00000350630; -.
DR BindingDB; Q9Y6L7; -.
DR ChEMBL; CHEMBL4295995; -.
DR DrugBank; DB01989; Methyl N-{[(1R)-1-({1-[(benzyloxy)carbonyl]-L-prolyl-6-ammonio-L-norleucyl}amino)-2-phenylethyl](hydroxy)phosphoryl}-L-alanyl-L-prolinate.
DR MEROPS; M12.018; -.
DR GlyConnect; 1820; 1 N-Linked glycan (1 site).
DR GlyCosmos; Q9Y6L7; 5 sites, 1 glycan.
DR GlyGen; Q9Y6L7; 9 sites, 1 N-linked glycan (1 site), 2 O-linked glycans (4 sites).
DR iPTMnet; Q9Y6L7; -.
DR PhosphoSitePlus; Q9Y6L7; -.
DR BioMuta; TLL2; -.
DR DMDM; 74762080; -.
DR MassIVE; Q9Y6L7; -.
DR MaxQB; Q9Y6L7; -.
DR PaxDb; 9606-ENSP00000350630; -.
DR PeptideAtlas; Q9Y6L7; -.
DR ProteomicsDB; 86720; -.
DR Antibodypedia; 53639; 56 antibodies from 19 providers.
DR DNASU; 7093; -.
DR Ensembl; ENST00000357947.4; ENSP00000350630.3; ENSG00000095587.9.
DR GeneID; 7093; -.
DR KEGG; hsa:7093; -.
DR MANE-Select; ENST00000357947.4; ENSP00000350630.3; NM_012465.4; NP_036597.1.
DR UCSC; uc001kml.3; human.
DR AGR; HGNC:11844; -.
DR CTD; 7093; -.
DR DisGeNET; 7093; -.
DR GeneCards; TLL2; -.
DR HGNC; HGNC:11844; TLL2.
DR HPA; ENSG00000095587; Tissue enhanced (brain, heart muscle, tongue).
DR MIM; 606743; gene.
DR neXtProt; NX_Q9Y6L7; -.
DR OpenTargets; ENSG00000095587; -.
DR PharmGKB; PA36546; -.
DR VEuPathDB; HostDB:ENSG00000095587; -.
DR eggNOG; KOG3714; Eukaryota.
DR GeneTree; ENSGT00940000160572; -.
DR HOGENOM; CLU_005140_0_0_1; -.
DR InParanoid; Q9Y6L7; -.
DR OMA; WTKQTVG; -.
DR OrthoDB; 2873870at2759; -.
DR PhylomeDB; Q9Y6L7; -.
DR TreeFam; TF314351; -.
DR PathwayCommons; Q9Y6L7; -.
DR Reactome; R-HSA-1474228; Degradation of the extracellular matrix.
DR Reactome; R-HSA-1650814; Collagen biosynthesis and modifying enzymes.
DR Reactome; R-HSA-2214320; Anchoring fibril formation.
DR Reactome; R-HSA-2243919; Crosslinking of collagen fibrils.
DR SignaLink; Q9Y6L7; -.
DR BioGRID-ORCS; 7093; 12 hits in 1152 CRISPR screens.
DR ChiTaRS; TLL2; human.
DR GeneWiki; TLL2; -.
DR GenomeRNAi; 7093; -.
DR Pharos; Q9Y6L7; Tchem.
DR PRO; PR:Q9Y6L7; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; Q9Y6L7; Protein.
DR Bgee; ENSG00000095587; Expressed in buccal mucosa cell and 114 other cell types or tissues.
DR Genevisible; Q9Y6L7; HS.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0004222; F:metalloendopeptidase activity; IBA:GO_Central.
DR GO; GO:0004252; F:serine-type endopeptidase activity; TAS:Reactome.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0030199; P:collagen fibril organization; TAS:Reactome.
DR GO; GO:0009953; P:dorsal/ventral pattern formation; IBA:GO_Central.
DR GO; GO:0048632; P:negative regulation of skeletal muscle tissue growth; IEA:Ensembl.
DR GO; GO:0016485; P:protein processing; IBA:GO_Central.
DR CDD; cd00041; CUB; 5.
DR CDD; cd00054; EGF_CA; 1.
DR CDD; cd04281; ZnMc_BMP1_TLD; 1.
DR Gene3D; 3.40.390.10; Collagenase (Catalytic Domain); 1.
DR Gene3D; 2.10.25.10; Laminin; 2.
DR Gene3D; 2.60.120.290; Spermadhesin, CUB domain; 5.
DR InterPro; IPR015446; BMP_1/tolloid-like.
DR InterPro; IPR000859; CUB_dom.
DR InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR InterPro; IPR000742; EGF-like_dom.
DR InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site.
DR InterPro; IPR018097; EGF_Ca-bd_CS.
DR InterPro; IPR024079; MetalloPept_cat_dom_sf.
DR InterPro; IPR001506; Peptidase_M12A.
DR InterPro; IPR006026; Peptidase_Metallo.
DR InterPro; IPR035914; Sperma_CUB_dom_sf.
DR InterPro; IPR034036; ZnMP_TLD/BMP1.
DR PANTHER; PTHR24255; COMPLEMENT COMPONENT 1, S SUBCOMPONENT-RELATED; 1.
DR PANTHER; PTHR24255:SF34; CUB AND SUSHI DOMAIN-CONTAINING PROTEIN 3 ISOFORM X1; 1.
DR Pfam; PF01400; Astacin; 1.
DR Pfam; PF00431; CUB; 5.
DR Pfam; PF07645; EGF_CA; 1.
DR Pfam; PF14670; FXa_inhibition; 1.
DR PIRSF; PIRSF001199; BMP_1/tolloid-like; 1.
DR PRINTS; PR00480; ASTACIN.
DR SMART; SM00042; CUB; 5.
DR SMART; SM00181; EGF; 2.
DR SMART; SM00179; EGF_CA; 2.
DR SMART; SM00235; ZnMc; 1.
DR SUPFAM; SSF57196; EGF/Laminin; 2.
DR SUPFAM; SSF55486; Metalloproteases ('zincins'), catalytic domain; 1.
DR SUPFAM; SSF49854; Spermadhesin, CUB domain; 5.
DR PROSITE; PS51864; ASTACIN; 1.
DR PROSITE; PS01180; CUB; 5.
DR PROSITE; PS01186; EGF_2; 2.
DR PROSITE; PS50026; EGF_3; 2.
DR PROSITE; PS01187; EGF_CA; 2.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 1: Evidence at protein level;
KW Calcium; Cleavage on pair of basic residues; Developmental protein;
KW Differentiation; Direct protein sequencing; Disulfide bond;
KW EGF-like domain; Glycoprotein; Hydrolase; Metal-binding; Metalloprotease;
KW Methylation; Protease; Reference proteome; Repeat; Secreted; Signal; Zinc;
KW Zymogen.
FT SIGNAL 1..25
FT /evidence="ECO:0000255"
FT PROPEP 26..149
FT /evidence="ECO:0000269|PubMed:10479448"
FT /id="PRO_0000046036"
FT CHAIN 150..1015
FT /note="Tolloid-like protein 2"
FT /id="PRO_0000046037"
FT DOMAIN 149..349
FT /note="Peptidase M12A"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT DOMAIN 351..463
FT /note="CUB 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
FT DOMAIN 464..576
FT /note="CUB 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
FT DOMAIN 576..617
FT /note="EGF-like 1; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 620..732
FT /note="CUB 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
FT DOMAIN 732..772
FT /note="EGF-like 2; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 776..888
FT /note="CUB 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
FT DOMAIN 889..1005
FT /note="CUB 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
FT REGION 24..49
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 88..130
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 88..113
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 243
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT BINDING 242
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT BINDING 246
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT BINDING 252
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT MOD_RES 963
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:Q9WVM6"
FT MOD_RES 966
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:Q9WVM6"
FT CARBOHYD 171
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 361
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 392
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 628
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 805
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 192..348
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT DISULFID 212..234
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT DISULFID 214..215
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01211"
FT DISULFID 351..377
FT /evidence="ECO:0000250"
FT DISULFID 404..426
FT /evidence="ECO:0000250"
FT DISULFID 464..490
FT /evidence="ECO:0000250"
FT DISULFID 517..539
FT /evidence="ECO:0000250"
FT DISULFID 580..592
FT /evidence="ECO:0000250"
FT DISULFID 588..601
FT /evidence="ECO:0000250"
FT DISULFID 603..616
FT /evidence="ECO:0000250"
FT DISULFID 620..646
FT /evidence="ECO:0000250"
FT DISULFID 673..695
FT /evidence="ECO:0000250"
FT DISULFID 736..747
FT /evidence="ECO:0000250"
FT DISULFID 743..756
FT /evidence="ECO:0000250"
FT DISULFID 758..771
FT /evidence="ECO:0000250"
FT DISULFID 776..802
FT /evidence="ECO:0000250"
FT DISULFID 829..851
FT /evidence="ECO:0000250"
FT DISULFID 889..919
FT /evidence="ECO:0000250"
FT DISULFID 946..968
FT /evidence="ECO:0000250"
FT CONFLICT 495
FT /note="T -> M (in Ref. 2; BAA76776)"
FT /evidence="ECO:0000305"
FT CONFLICT 576..593
FT /note="EVDECSWPDHGGCEHRCV -> GKKKKKKKKKKKKKKKKK (in Ref. 5;
FT AAH13871)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1015 AA; 113557 MW; 25F5B23065861593 CRC64;
MPRATALGAL VSLLLLLPLP RGAGGLGERP DATADYSELD GEEGTEQQLE HYHDPCKAAV
FWGDIALDED DLKLFHIDKA RDWTKQTVGA TGHSTGGLEE QASESSPDTT AMDTGTKEAG
KDGRENTTLL HSPGTLHAAA KTFSPRVRRA TTSRTERIWP GGVIPYVIGG NFTGSQRAIF
KQAMRHWEKH TCVTFIERTD EESFIVFSYR TCGCCSYVGR RGGGPQAISI GKNCDKFGIV
AHELGHVVGF WHEHTRPDRD QHVTIIRENI QPGQEYNFLK MEAGEVSSLG ETYDFDSIMH
YARNTFSRGV FLDTILPRQD DNGVRPTIGQ RVRLSQGDIA QARKLYKCPA CGETLQDTTG
NFSAPGFPNG YPSYSHCVWR ISVTPGEKIV LNFTSMDLFK SRLCWYDYVE VRDGYWRKAP
LLGRFCGDKI PEPLVSTDSR LWVEFRSSSN ILGKGFFAAY EATCGGDMNK DAGQIQSPNY
PDDYRPSKEC VWRITVSEGF HVGLTFQAFE IERHDSCAYD YLEVRDGPTE ESALIGHFCG
YEKPEDVKSS SNRLWMKFVS DGSINKAGFA ANFFKEVDEC SWPDHGGCEH RCVNTLGSYK
CACDPGYELA ADKKMCEVAC GGFITKLNGT ITSPGWPKEY PTNKNCVWQV VAPAQYRISL
QFEVFELEGN DVCKYDFVEV RSGLSPDAKL HGRFCGSETP EVITSQSNNM RVEFKSDNTV
SKRGFRAHFF SDKDECAKDN GGCQHECVNT FGSYLCRCRN GYWLHENGHD CKEAGCAHKI
SSVEGTLASP NWPDKYPSRR ECTWNISSTA GHRVKLTFNE FEIEQHQECA YDHLEMYDGP
DSLAPILGRF CGSKKPDPTV ASGSSMFLRF YSDASVQRKG FQAVHSTECG GRLKAEVQTK
ELYSHAQFGD NNYPSEARCD WVIVAEDGYG VELTFRTFEV EEEADCGYDY MEAYDGYDSS
APRLGRFCGS GPLEEIYSAG DSLMIRFRTD DTINKKGFHA RYTSTKFQDA LHMKK
//
