O43897 (TLL1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tolloid-like protein 1
EC=3.4.24.-

Gene names

Name:	TLL1
Synonyms:	TLL

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1013 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Protease which processes procollagen C-propeptides, such as chordin, pro-biglycan and pro-lysyl oxidase. Required for the embryonic development. Predominant protease, which in the development, influences dorsal-ventral patterning and skeletogenesis.
Cofactor	Binds 1 zinc ion per subunit By similarity.
Subcellular location	Secreted Probable.
Involvement in disease	Atrial septal defect 6 (ASD6) [MIM:613087]: A congenital heart malformation characterized by incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10
Sequence similarities	Belongs to the peptidase M12A family. Contains 5 CUB domains. Contains 2 EGF-like domains.

Ontologies

Keywords
Biological process	Differentiation
Cellular component	Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Atrial septal defect Disease mutation
Domain	EGF-like domain Repeat Signal
Ligand	Calcium Metal-binding Zinc
Molecular function	Developmental protein Hydrolase Metalloprotease Protease
PTM	Disulfide bond Glycoprotein Zymogen
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW extracellular matrix organization Traceable author statement. Source: Reactome proteolysis Inferred from electronic annotation. Source: UniProtKB-KW skeletal system development Traceable author statement PubMed 8661043. Source: ProtInc
Cellular_component	extracellular region Traceable author statement. Source: Reactome
Molecular_function	calcium ion binding Inferred from electronic annotation. Source: InterPro metalloendopeptidase activity Inferred from electronic annotation. Source: InterPro zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O43897-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: O43897-2)

The sequence of this isoform differs from the canonical sequence as follows:
     387-392: IVLNFT → VVFSLC
     393-1013: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 30

30

Potential

Propeptide

31 – 147

117

Potential

PRO_0000046023

Chain

148 – 1013

866

Tolloid-like protein 1

PRO_0000046024

Regions

Domain

349 – 461

113

CUB 1

Domain

462 – 574

113

CUB 2

Domain

574 – 615

42

EGF-like 1; calcium-binding Potential

Domain

618 – 730

113

CUB 3

Domain

730 – 770

41

EGF-like 2; calcium-binding Potential

Domain

774 – 886

113

CUB 4

Domain

887 – 1003

117

CUB 5

Region

148 – 348

201

Metalloprotease By similarity

Sites

Active site

241

1

By similarity

Metal binding

240

1

Zinc; catalytic By similarity

Metal binding

244

1

Zinc; catalytic By similarity

Metal binding

250

1

Zinc; catalytic By similarity

Amino acid modifications

Glycosylation

169

1

N-linked (GlcNAc...) Potential

Glycosylation

359

1

N-linked (GlcNAc...) Potential

Glycosylation

390

1

N-linked (GlcNAc...) Potential

Glycosylation

626

1

N-linked (GlcNAc...) Potential

Disulfide bond

190 ↔ 346

Ref.8

Disulfide bond

210 ↔ 232

By similarity

Disulfide bond

212 ↔ 213

By similarity

Disulfide bond

349 ↔ 375

By similarity

Disulfide bond

402 ↔ 424

By similarity

Disulfide bond

462 ↔ 488

By similarity

Disulfide bond

515 ↔ 537

By similarity

Disulfide bond

578 ↔ 590

By similarity

Disulfide bond

586 ↔ 599

By similarity

Disulfide bond

601 ↔ 614

By similarity

Disulfide bond

618 ↔ 644

By similarity

Disulfide bond

671 ↔ 693

By similarity

Disulfide bond

734 ↔ 745

By similarity

Disulfide bond

741 ↔ 754

By similarity

Disulfide bond

756 ↔ 769

By similarity

Disulfide bond

774 ↔ 800

By similarity

Disulfide bond

827 ↔ 849

By similarity

Disulfide bond

887 ↔ 917

By similarity

Disulfide bond

944 ↔ 966

By similarity

Natural variations

Alternative sequence

387 – 392

6

IVLNFT → VVFSLC in isoform 2.

VSP_017197

Alternative sequence

393 – 1013

621

Missing in isoform 2.

VSP_017198

Natural variant

182

1

M → L in ASD6. Ref.10

VAR_062519

Natural variant

238

1

V → A in ASD6. Ref.10

VAR_062520

Natural variant

629

1

I → V in ASD6. Ref.10

VAR_062521

Natural variant

688

1

L → V in a breast cancer sample; somatic mutation. Ref.9

VAR_036142

Natural variant

958

1

T → A.
Corresponds to variant rs2291822 [ dbSNP | Ensembl ].

VAR_051585

Experimental info

Sequence conflict

156

1

I → V in AAF86287. Ref.2

Sequence conflict

221

1

N → S in AAF86287. Ref.2

Sequence conflict

284

1

V → A in AAF86287. Ref.2

Secondary structure

1

.

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1013

Helix Strand Turn

Details...

Helix

153 – 155

3

Helix

158 – 160

3

Beta strand

161 – 166

6

Helix

172 – 188

17

Beta strand

192 – 195

4

Beta strand

203 – 206

4

Beta strand

224 – 227

4

Helix

235 – 246

12

Helix

251 – 253

3

Helix

257 – 259

3

Beta strand

261 – 263

3

Helix

265 – 267

3

Helix

273 – 276

4

Helix

281 – 283

3

Turn

301 – 304

4

Beta strand

305 – 307

3

Beta strand

312 – 315

4

Helix

334 – 343

10

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified June 1, 1998. Version 1. Checksum: 0FDDB6E8E9032DCC	FASTA	1,013	114,709
	10 20 30 40 50 60 MGLGTLSPRM LVWLVASGIV FYGELWVCAG LDYDYTFDGN EEDKTETIDY KDPCKAAVFW 70 80 90 100 110 120 GDIALDDEDL NIFQIDRTID LTQNPFGNLG HTTGGLGDHA MSKKRGALYQ LIDRIRRIGF 130 140 150 160 170 180 GLEQNNTVKG KVPLQFSGQN EKNRVPRAAT SRTERIWPGG VIPYVIGGNF TGSQRAMFKQ 190 200 210 220 230 240 AMRHWEKHTC VTFIERSDEE SYIVFTYRPC GCCSYVGRRG NGPQAISIGK NCDKFGIVVH 250 260 270 280 290 300 ELGHVIGFWH EHTRPDRDNH VTIIRENIQP GQEYNFLKME PGEVNSLGER YDFDSIMHYA 310 320 330 340 350 360 RNTFSRGMFL DTILPSRDDN GIRPAIGQRT RLSKGDIAQA RKLYRCPACG ETLQESNGNL 370 380 390 400 410 420 SSPGFPNGYP SYTHCIWRVS VTPGEKIVLN FTTMDLYKSS LCWYDYIEVR DGYWRKSPLL 430 440 450 460 470 480 GRFCGDKLPE VLTSTDSRMW IEFRSSSNWV GKGFAAVYEA ICGGEIRKNE GQIQSPNYPD 490 500 510 520 530 540 DYRPMKECVW KITVSESYHV GLTFQSFEIE RHDNCAYDYL EVRDGTSENS PLIGRFCGYD 550 560 570 580 590 600 KPEDIRSTSN TLWMKFVSDG TVNKAGFAAN FFKEEDECAK PDRGGCEQRC LNTLGSYQCA 610 620 630 640 650 660 CEPGYELGPD RRSCEAACGG LLTKLNGTIT TPGWPKEYPP NKNCVWQVVA PTQYRISVKF 670 680 690 700 710 720 EFFELEGNEV CKYDYVEIWS GLSSESKLHG KFCGAEVPEV ITSQFNNMRI EFKSDNTVSK 730 740 750 760 770 780 KGFKAHFFSD KDECSKDNGG CQHECVNTMG SYMCQCRNGF VLHDNKHDCK EAECEQKIHS 790 800 810 820 830 840 PSGLITSPNW PDKYPSRKEC TWEISATPGH RIKLAFSEFE IEQHQECAYD HLEVFDGETE 850 860 870 880 890 900 KSPILGRLCG NKIPDPLVAT GNKMFVRFVS DASVQRKGFQ ATHSTECGGR LKAESKPRDL 910 920 930 940 950 960 YSHAQFGDNN YPGQVDCEWL LVSERGSRLE LSFQTFEVEE EADCGYDYVE LFDGLDSTAV 970 980 990 1000 1010 GLGRFCGSGP PEEIYSIGDS VLIHFHTDDT INKKGFHIRY KSIRYPDTTH TKK
	Isoform 2 [UniParc]. Checksum: B240EB78AD353BFE	FASTA	392	44,186
	10 20 30 40 50 60 MGLGTLSPRM LVWLVASGIV FYGELWVCAG LDYDYTFDGN EEDKTETIDY KDPCKAAVFW 70 80 90 100 110 120 GDIALDDEDL NIFQIDRTID LTQNPFGNLG HTTGGLGDHA MSKKRGALYQ LIDRIRRIGF 130 140 150 160 170 180 GLEQNNTVKG KVPLQFSGQN EKNRVPRAAT SRTERIWPGG VIPYVIGGNF TGSQRAMFKQ 190 200 210 220 230 240 AMRHWEKHTC VTFIERSDEE SYIVFTYRPC GCCSYVGRRG NGPQAISIGK NCDKFGIVVH 250 260 270 280 290 300 ELGHVIGFWH EHTRPDRDNH VTIIRENIQP GQEYNFLKME PGEVNSLGER YDFDSIMHYA 310 320 330 340 350 360 RNTFSRGMFL DTILPSRDDN GIRPAIGQRT RLSKGDIAQA RKLYRCPACG ETLQESNGNL 370 380 390 SSPGFPNGYP SYTHCIWRVS VTPGEKVVFS LC

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Sequence of human mammalian tolloid-like (mTll) and chromosomal localization of the cognate gene TLL." Greenspan D.S., Takahara K. Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Placenta.
[2]	"Human cardiac/brain tolloid-like protein." Arleth A.J., Elshourbagy N.A., Li X., Willette R.N. Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Heart.
[3]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). Tissue: Prostate.
[5]	"Mammalian BMP-1/Tolloid-related metalloproteinases, including novel family member mammalian Tolloid-like 2, have differential enzymatic activities and distributions of expression relevant to patterning and skeletogenesis." Scott I.C., Blitz I.L., Pappano W.N., Imamura Y., Clark T.G., Steiglitz B.M., Thomas C.L., Maas S.A., Takahara K., Cho K.W., Greenspan D.S. Dev. Biol. 213:283-300(1999) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF ACTION ON COLLAGENS.
[6]	"Bone morphogenetic protein-1 processes probiglycan." Scott I.C., Imamura Y., Pappano W.N., Troedel J.M., Recklies A.D., Roughley P.J., Greenspan D.S. J. Biol. Chem. 275:30504-30511(2000) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF ACTION ON PROBIGLYCAN.
[7]	"Multiple bone morphogenetic protein 1-related mammalian metalloproteinases process pro-lysyl oxidase at the correct physiological site and control lysyl oxidase activation in mouse embryo fibroblast cultures." Uzel M.I., Scott I.C., Babakhanlou-Chase H., Palamakumbura A.H., Pappano W.N., Hong H.-H., Greenspan D.S., Trackman P.C. J. Biol. Chem. 276:22537-22543(2001) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF ACTION ON PRO-LYSYL OXIDASE.
[8]	"Structural basis for the substrate specificity of bone morphogenetic protein 1/tolloid-like metalloproteases." Mac Sweeney A., Gil-Parrado S., Vinzenz D., Bernardi A., Hein A., Bodendorf U., Erbel P., Logel C., Gerhartz B. J. Mol. Biol. 384:228-239(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS) OF 148-348, DISULFIDE BONDS.
[9]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] VAL-688.
[10]	"Mutations in mammalian tolloid-like 1 gene detected in adult patients with ASD." Stanczak P., Witecka J., Szydlo A., Gutmajster E., Lisik M., Augusciak-Duma A., Tarnowski M., Czekaj T., Czekaj H., Sieron A.L. Eur. J. Hum. Genet. 17:344-351(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS ASD6 LEU-182; ALA-238 AND VAL-629.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U91963 mRNA. Translation: AAB93878.1.
AF282732 mRNA. Translation: AAF86287.1.
CH471056 Genomic DNA. Translation: EAX04813.1.
BC016922 mRNA. Translation: AAH16922.1.
BC136429 mRNA. Translation: AAI36430.1.
BC136430 mRNA. Translation: AAI36431.1.

IPI

IPI00018381.
IPI00718863.

RefSeq

NP_001191689.1. NM_001204760.1.
NP_036596.3. NM_012464.4.

UniGene

Hs.106513.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3EDI	X-ray	1.40	A	148-348	[»]

ProteinModelPortal

O43897.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000061240.

Protein family/group databases

MEROPS

M12.016.

PTM databases

PhosphoSite

O43897.

Proteomic databases

PaxDb

O43897.

PRIDE

O43897.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000061240; ENSP00000061240; ENSG00000038295.
ENST00000513213; ENSP00000422937; ENSG00000038295.

GeneID

7092.

KEGG

hsa:7092.

UCSC

uc003irh.2. human.
uc021xud.1. human.

Organism-specific databases

CTD

7092.

GeneCards

GC04P166794.

HGNC

HGNC:11843. TLL1.

MIM

606742. gene.
613087. phenotype.

neXtProt

NX_O43897.

Orphanet

99106. Atrial septal defect, ostium primum type.
99103. Atrial septal defect, ostium secundum type.

PharmGKB

PA36545.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG70307.

HOGENOM

HOG000236339.

HOVERGEN

HBG004859.

InParanoid

O43897.

KO

K09608.

OrthoDB

EOG4FTVZV.

PhylomeDB

O43897.

Enzyme and pathway databases

Reactome

REACT_118779. Extracellular matrix organization.

Gene expression databases

ArrayExpress

O43897.

Bgee

O43897.

CleanEx

HS_TLL1.

Genevestigator

O43897.

Family and domain databases

Gene3D

2.60.120.290. 5 hits.
3.40.390.10. 1 hit.

InterPro

IPR015446. BMP_1/tolloid-like.
IPR000859. CUB_dom.
IPR000742. EG-like_dom.
IPR001881. EGF-like_Ca-bd.
IPR013032. EGF-like_CS.
IPR000152. EGF-type_Asp/Asn_hydroxyl_site.
IPR018097. EGF_Ca-bd_CS.
IPR024079. MetalloPept_cat_dom.
IPR001506. Peptidase_M12A.
IPR006026. Peptidase_Metallo.
[Graphical view]

Pfam

PF01400. Astacin. 1 hit.
PF00431. CUB. 5 hits.
PF07645. EGF_CA. 1 hit.
[Graphical view]

PIRSF

PIRSF001199. BMP_1/tolloid-like. 1 hit.

PRINTS

PR00480. ASTACIN.

SMART

SM00042. CUB. 5 hits.
SM00179. EGF_CA. 2 hits.
SM00235. ZnMc. 1 hit.
[Graphical view]

SUPFAM

SSF49854. CUB. 5 hits.

PROSITE

PS01180. CUB. 5 hits.
PS00022. EGF_1. False negative.
PS01186. EGF_2. 2 hits.
PS50026. EGF_3. 2 hits.
PS01187. EGF_CA. 2 hits.
PS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

O43897.

GenomeRNAi

7092.

NextBio

27743.

SOURCE

Search...

Entry information

Entry name

TLL1_HUMAN

Accession

Primary (citable) accession number: O43897
Secondary accession number(s): B2RMU2, Q96AN3, Q9NQS4

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 7, 2006
Last sequence update:	June 1, 1998
Last modified:	May 1, 2013
This is version 98 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.