ID TLL1_HUMAN Reviewed; 1013 AA. AC O43897; B2RMU2; Q96AN3; Q9NQS4; DT 07-FEB-2006, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-1998, sequence version 1. DT 13-FEB-2019, entry version 144. DE RecName: Full=Tolloid-like protein 1; DE EC=3.4.24.-; DE Flags: Precursor; GN Name=TLL1; Synonyms=TLL; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Placenta; RA Greenspan D.S., Takahara K.; RT "Sequence of human mammalian tolloid-like (mTll) and chromosomal RT localization of the cognate gene TLL."; RL Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Heart; RA Arleth A.J., Elshourbagy N.A., Li X., Willette R.N.; RT "Human cardiac/brain tolloid-like protein."; RL Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Prostate; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP CHARACTERIZATION OF ACTION ON COLLAGENS. 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 RT family member mammalian Tolloid-like 2, have differential enzymatic RT activities and distributions of expression relevant to patterning and RT skeletogenesis."; RL Dev. Biol. 213:283-300(1999). RN [6] RP CHARACTERIZATION OF ACTION ON PROBIGLYCAN. RX PubMed=10896944; DOI=10.1074/jbc.M004846200; RA Scott I.C., Imamura Y., Pappano W.N., Troedel J.M., Recklies A.D., RA Roughley P.J., Greenspan D.S.; RT "Bone morphogenetic protein-1 processes probiglycan."; RL J. Biol. Chem. 275:30504-30511(2000). RN [7] RP CHARACTERIZATION OF ACTION ON PRO-LYSYL OXIDASE. 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 RT metalloproteinases process pro-lysyl oxidase at the correct RT physiological site and control lysyl oxidase activation in mouse RT embryo fibroblast cultures."; RL J. Biol. Chem. 276:22537-22543(2001). RN [8] RP X-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS) OF 148-348, AND DISULFIDE BONDS. RX PubMed=18824173; DOI=10.1016/j.jmb.2008.09.029; RA Mac Sweeney A., Gil-Parrado S., Vinzenz D., Bernardi A., Hein A., RA Bodendorf U., Erbel P., Logel C., Gerhartz B.; RT "Structural basis for the substrate specificity of bone morphogenetic RT protein 1/tolloid-like metalloproteases."; RL J. Mol. Biol. 384:228-239(2008). RN [9] RP VARIANT [LARGE SCALE ANALYSIS] VAL-688. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C., RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., RA Vogelstein B., Kinzler K.W., Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal RT cancers."; RL Science 314:268-274(2006). RN [10] RP VARIANTS ASD6 LEU-182; ALA-238 AND VAL-629. RX PubMed=18830233; DOI=10.1038/ejhg.2008.175; RA Stanczak P., Witecka J., Szydlo A., Gutmajster E., Lisik M., RA Augusciak-Duma A., Tarnowski M., Czekaj T., Czekaj H., Sieron A.L.; RT "Mutations in mammalian tolloid-like 1 gene detected in adult patients RT with ASD."; RL Eur. J. Hum. Genet. 17:344-351(2009). CC -!- FUNCTION: Protease which processes procollagen C-propeptides, such CC as chordin, pro-biglycan and pro-lysyl oxidase. Required for the CC embryonic development. Predominant protease, which in the CC 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 -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=O43897-1; Sequence=Displayed; CC Name=2; CC IsoId=O43897-2; Sequence=VSP_017197, VSP_017198; CC Note=No experimental confirmation available.; CC -!- DISEASE: Atrial septal defect 6 (ASD6) [MIM:613087]: A congenital CC heart malformation characterized by incomplete closure of the wall CC between the atria resulting in blood flow from the left to the CC right atria. {ECO:0000269|PubMed:18830233}. Note=The disease is CC caused by mutations affecting the gene represented in this entry. 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; U91963; AAB93878.1; -; mRNA. DR EMBL; AF282732; AAF86287.1; -; mRNA. DR EMBL; CH471056; EAX04813.1; -; Genomic_DNA. DR EMBL; BC016922; AAH16922.1; -; mRNA. DR EMBL; BC136429; AAI36430.1; -; mRNA. DR EMBL; BC136430; AAI36431.1; -; mRNA. DR CCDS; CCDS3811.1; -. [O43897-1] DR CCDS; CCDS56342.1; -. [O43897-2] DR RefSeq; NP_001191689.1; NM_001204760.1. [O43897-2] DR RefSeq; NP_036596.3; NM_012464.4. [O43897-1] DR UniGene; Hs.106513; -. DR PDB; 3EDI; X-ray; 1.40 A; A=148-348. DR PDBsum; 3EDI; -. DR ProteinModelPortal; O43897; -. DR SMR; O43897; -. DR BioGrid; 112947; 3. DR STRING; 9606.ENSP00000061240; -. DR MEROPS; M12.016; -. DR GlyConnect; 1819; -. DR iPTMnet; O43897; -. DR PhosphoSitePlus; O43897; -. DR BioMuta; TLL1; -. DR MaxQB; O43897; -. DR PaxDb; O43897; -. DR PeptideAtlas; O43897; -. DR PRIDE; O43897; -. DR ProteomicsDB; 49221; -. DR ProteomicsDB; 49222; -. [O43897-2] DR Ensembl; ENST00000061240; ENSP00000061240; ENSG00000038295. [O43897-1] DR Ensembl; ENST00000513213; ENSP00000422937; ENSG00000038295. [O43897-2] DR GeneID; 7092; -. DR KEGG; hsa:7092; -. DR UCSC; uc003irh.3; human. [O43897-1] DR CTD; 7092; -. DR DisGeNET; 7092; -. DR EuPathDB; HostDB:ENSG00000038295.7; -. DR GeneCards; TLL1; -. DR HGNC; HGNC:11843; TLL1. DR HPA; HPA060767; -. DR MalaCards; TLL1; -. DR MIM; 606742; gene. DR MIM; 613087; phenotype. DR neXtProt; NX_O43897; -. DR OpenTargets; ENSG00000038295; -. DR Orphanet; 99106; Atrial septal defect, ostium primum type. DR Orphanet; 99103; Atrial septal defect, ostium secundum type. DR PharmGKB; PA36545; -. DR eggNOG; KOG3714; Eukaryota. DR eggNOG; ENOG410ZPX7; LUCA. DR GeneTree; ENSGT00940000157225; -. DR HOGENOM; HOG000236339; -. DR HOVERGEN; HBG004859; -. DR InParanoid; O43897; -. DR KO; K09608; -. DR OrthoDB; 170905at2759; -. DR PhylomeDB; O43897; -. DR TreeFam; TF314351; -. 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 EvolutionaryTrace; O43897; -. DR GeneWiki; TLL1; -. DR GenomeRNAi; 7092; -. DR PRO; PR:O43897; -. DR Proteomes; UP000005640; Chromosome 4. DR Bgee; ENSG00000038295; Expressed in 94 organ(s), highest expression level in secondary oocyte. DR ExpressionAtlas; O43897; baseline and differential. DR Genevisible; O43897; HS. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro. DR GO; GO:0004222; F:metalloendopeptidase activity; TAS:Reactome. 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:0022617; P:extracellular matrix disassembly; TAS:Reactome. DR GO; GO:0001501; P:skeletal system development; TAS:ProtInc. DR CDD; cd00041; CUB; 5. DR CDD; cd04281; ZnMc_BMP1_TLD; 1. DR Gene3D; 2.60.120.290; -; 5. DR Gene3D; 3.40.390.10; -; 1. DR InterPro; IPR015446; BMP_1/tolloid-like. DR InterPro; IPR000859; CUB_dom. DR InterPro; IPR001881; EGF-like_Ca-bd_dom. DR InterPro; IPR013032; EGF-like_CS. 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 Pfam; PF01400; Astacin; 1. DR Pfam; PF00431; CUB; 5. DR Pfam; PF07645; EGF_CA; 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; SSF49854; SSF49854; 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 3D-structure; Alternative splicing; Atrial septal defect; Calcium; KW Complete proteome; Developmental protein; Differentiation; KW Disease mutation; Disulfide bond; EGF-like domain; Glycoprotein; KW Hydrolase; Metal-binding; Metalloprotease; Polymorphism; Protease; KW Reference proteome; Repeat; Secreted; Signal; Zinc; Zymogen. FT SIGNAL 1 30 {ECO:0000255}. FT PROPEP 31 147 {ECO:0000255}. FT /FTId=PRO_0000046023. FT CHAIN 148 1013 Tolloid-like protein 1. FT /FTId=PRO_0000046024. FT DOMAIN 148 347 Peptidase M12A. {ECO:0000255|PROSITE- FT ProRule:PRU01211}. FT DOMAIN 349 461 CUB 1. {ECO:0000255|PROSITE- FT ProRule:PRU00059}. FT DOMAIN 462 574 CUB 2. {ECO:0000255|PROSITE- FT ProRule:PRU00059}. FT DOMAIN 574 615 EGF-like 1; calcium-binding. FT {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DOMAIN 618 730 CUB 3. {ECO:0000255|PROSITE- FT ProRule:PRU00059}. FT DOMAIN 730 770 EGF-like 2; calcium-binding. FT {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DOMAIN 774 886 CUB 4. {ECO:0000255|PROSITE- FT ProRule:PRU00059}. FT DOMAIN 887 1003 CUB 5. {ECO:0000255|PROSITE- FT ProRule:PRU00059}. FT ACT_SITE 241 241 {ECO:0000255|PROSITE-ProRule:PRU01211}. FT METAL 240 240 Zinc; via tele nitrogen; catalytic. FT {ECO:0000255|PROSITE-ProRule:PRU01211}. FT METAL 244 244 Zinc; via tele nitrogen; catalytic. FT {ECO:0000255|PROSITE-ProRule:PRU01211}. FT METAL 250 250 Zinc; via tele nitrogen; catalytic. FT {ECO:0000255|PROSITE-ProRule:PRU01211}. FT CARBOHYD 169 169 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 359 359 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 390 390 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 626 626 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT DISULFID 190 346 {ECO:0000255|PROSITE-ProRule:PRU01211, FT ECO:0000269|PubMed:18824173}. FT DISULFID 210 232 {ECO:0000255|PROSITE-ProRule:PRU01211}. FT DISULFID 212 213 {ECO:0000255|PROSITE-ProRule:PRU01211}. FT DISULFID 349 375 {ECO:0000250}. FT DISULFID 402 424 {ECO:0000250}. FT DISULFID 462 488 {ECO:0000250}. FT DISULFID 515 537 {ECO:0000250}. FT DISULFID 578 590 {ECO:0000250}. FT DISULFID 586 599 {ECO:0000250}. FT DISULFID 601 614 {ECO:0000250}. FT DISULFID 618 644 {ECO:0000250}. FT DISULFID 671 693 {ECO:0000250}. FT DISULFID 734 745 {ECO:0000250}. FT DISULFID 741 754 {ECO:0000250}. FT DISULFID 756 769 {ECO:0000250}. FT DISULFID 774 800 {ECO:0000250}. FT DISULFID 827 849 {ECO:0000250}. FT DISULFID 887 917 {ECO:0000250}. FT DISULFID 944 966 {ECO:0000250}. FT VAR_SEQ 387 392 IVLNFT -> VVFSLC (in isoform 2). FT {ECO:0000303|PubMed:15489334}. FT /FTId=VSP_017197. FT VAR_SEQ 393 1013 Missing (in isoform 2). FT {ECO:0000303|PubMed:15489334}. FT /FTId=VSP_017198. FT VARIANT 182 182 M -> L (in ASD6; dbSNP:rs137852951). FT {ECO:0000269|PubMed:18830233}. FT /FTId=VAR_062519. FT VARIANT 238 238 V -> A (in ASD6; dbSNP:rs137852952). FT {ECO:0000269|PubMed:18830233}. FT /FTId=VAR_062520. FT VARIANT 629 629 I -> V (in ASD6; dbSNP:rs137852953). FT {ECO:0000269|PubMed:18830233}. FT /FTId=VAR_062521. FT VARIANT 688 688 L -> V (in a breast cancer sample; FT somatic mutation). FT {ECO:0000269|PubMed:16959974}. FT /FTId=VAR_036142. FT VARIANT 958 958 T -> A (in dbSNP:rs2291822). FT /FTId=VAR_051585. FT CONFLICT 156 156 I -> V (in Ref. 2; AAF86287). FT {ECO:0000305}. FT CONFLICT 221 221 N -> S (in Ref. 2; AAF86287). FT {ECO:0000305}. FT CONFLICT 284 284 V -> A (in Ref. 2; AAF86287). FT {ECO:0000305}. FT HELIX 153 155 {ECO:0000244|PDB:3EDI}. FT HELIX 158 160 {ECO:0000244|PDB:3EDI}. FT STRAND 161 166 {ECO:0000244|PDB:3EDI}. FT HELIX 172 188 {ECO:0000244|PDB:3EDI}. FT STRAND 192 195 {ECO:0000244|PDB:3EDI}. FT STRAND 203 206 {ECO:0000244|PDB:3EDI}. FT STRAND 224 227 {ECO:0000244|PDB:3EDI}. FT HELIX 235 246 {ECO:0000244|PDB:3EDI}. FT HELIX 251 253 {ECO:0000244|PDB:3EDI}. FT HELIX 257 259 {ECO:0000244|PDB:3EDI}. FT STRAND 261 263 {ECO:0000244|PDB:3EDI}. FT HELIX 265 267 {ECO:0000244|PDB:3EDI}. FT HELIX 273 276 {ECO:0000244|PDB:3EDI}. FT HELIX 281 283 {ECO:0000244|PDB:3EDI}. FT TURN 301 304 {ECO:0000244|PDB:3EDI}. FT STRAND 305 307 {ECO:0000244|PDB:3EDI}. FT STRAND 312 315 {ECO:0000244|PDB:3EDI}. FT HELIX 334 343 {ECO:0000244|PDB:3EDI}. SQ SEQUENCE 1013 AA; 114709 MW; 0FDDB6E8E9032DCC CRC64; MGLGTLSPRM LVWLVASGIV FYGELWVCAG LDYDYTFDGN EEDKTETIDY KDPCKAAVFW GDIALDDEDL NIFQIDRTID LTQNPFGNLG HTTGGLGDHA MSKKRGALYQ LIDRIRRIGF GLEQNNTVKG KVPLQFSGQN EKNRVPRAAT SRTERIWPGG VIPYVIGGNF TGSQRAMFKQ AMRHWEKHTC VTFIERSDEE SYIVFTYRPC GCCSYVGRRG NGPQAISIGK NCDKFGIVVH ELGHVIGFWH EHTRPDRDNH VTIIRENIQP GQEYNFLKME PGEVNSLGER YDFDSIMHYA RNTFSRGMFL DTILPSRDDN GIRPAIGQRT RLSKGDIAQA RKLYRCPACG ETLQESNGNL SSPGFPNGYP SYTHCIWRVS VTPGEKIVLN FTTMDLYKSS LCWYDYIEVR DGYWRKSPLL GRFCGDKLPE VLTSTDSRMW IEFRSSSNWV GKGFAAVYEA ICGGEIRKNE GQIQSPNYPD DYRPMKECVW KITVSESYHV GLTFQSFEIE RHDNCAYDYL EVRDGTSENS PLIGRFCGYD KPEDIRSTSN TLWMKFVSDG TVNKAGFAAN FFKEEDECAK PDRGGCEQRC LNTLGSYQCA CEPGYELGPD RRSCEAACGG LLTKLNGTIT TPGWPKEYPP NKNCVWQVVA PTQYRISVKF EFFELEGNEV CKYDYVEIWS GLSSESKLHG KFCGAEVPEV ITSQFNNMRI EFKSDNTVSK KGFKAHFFSD KDECSKDNGG CQHECVNTMG SYMCQCRNGF VLHDNKHDCK EAECEQKIHS PSGLITSPNW PDKYPSRKEC TWEISATPGH RIKLAFSEFE IEQHQECAYD HLEVFDGETE KSPILGRLCG NKIPDPLVAT GNKMFVRFVS DASVQRKGFQ ATHSTECGGR LKAESKPRDL YSHAQFGDNN YPGQVDCEWL LVSERGSRLE LSFQTFEVEE EADCGYDYVE LFDGLDSTAV GLGRFCGSGP PEEIYSIGDS VLIHFHTDDT INKKGFHIRY KSIRYPDTTH TKK //