Reviewed, UniProtKB/Swiss-Prot P07204 (TRBM_HUMAN)

Names and origin

Protein names

Recommended name:
    Thrombomodulin
      Short name=TM
Alternative name(s):
    Fetomodulin
    CD_antigen=CD141

Gene names

Name:	THBD
Synonyms:	THRM

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	575 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	Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated.
Subcellular location	Membrane; Single-pass type I membrane protein.
Tissue specificity	Endothelial cells are unique in synthesizing thrombomodulin.
Post-translational modification	N-glycosylated. Ref.8 The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains.
Involvement in disease	Defects in THBD are the cause of thrombophilia due to thrombomodulin defect (THR-THBDD) [MIM:188040]. THR-THBDD is a hemostatic disorder characterized by a tendency to thrombosis. Ref.15 Ref.16 Ref.20
Sequence similarities	Contains 1 C-type lectin domain. Contains 6 EGF-like domains.

Ontologies

Keywords
Biological process	Blood coagulation
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation Thrombophilia
Domain	EGF-like domain Repeat Signal Transmembrane
Molecular function	Receptor
PTM	Disulfide bond Glycoprotein Hydroxylation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	blood coagulation Traceable author statement. Source: ProtInc
Cellular component	integral to plasma membrane Ref.2 Traceable author statement. Source: ProtInc
Molecular function	calcium ion binding Traceable author statement. Source: ProtInc protein binding Inferred from physical interaction. Source: IntAct transmembrane receptor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
F2	P00734	1	EBI-941422,EBI-297094

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 18

18

Ref.1

Chain

19 – 575

557

Thrombomodulin

PRO_0000007771

Regions

Topological domain

19 – 515

497

Extracellular Potential

Transmembrane

516 – 539

24

Potential

Topological domain

540 – 575

36

Cytoplasmic Potential

Domain

31 – 169

139

C-type lectin

Domain

241 – 281

41

EGF-like 1

Domain

284 – 324

41

EGF-like 2

Domain

325 – 363

39

EGF-like 3; calcium-binding Potential

Domain

365 – 405

41

EGF-like 4

Domain

404 – 440

37

EGF-like 5

Domain

441 – 481

41

EGF-like 6; calcium-binding Potential

Amino acid modifications

Modified residue

342

1

(3R)-3-hydroxyasparagine

Glycosylation

47

1

N-linked (GlcNAc...) Potential

Glycosylation

115

1

N-linked (GlcNAc...) Potential

Glycosylation

116

1

N-linked (GlcNAc...) Potential

Glycosylation

382

1

N-linked (GlcNAc...) Potential

Glycosylation

409

1

N-linked (GlcNAc...) Potential

Glycosylation

490

1

O-linked (Xyl...) (chondroitin sulfate)

Glycosylation

492

1

O-linked (Xyl...) (chondroitin sulfate) Ref.8

Disulfide bond

137 ↔ 158

By similarity

Disulfide bond

245 ↔ 256

By similarity

Disulfide bond

252 ↔ 265

By similarity

Disulfide bond

267 ↔ 280

By similarity

Disulfide bond

288 ↔ 296

By similarity

Disulfide bond

292 ↔ 308

By similarity

Disulfide bond

310 ↔ 323

By similarity

Disulfide bond

329 ↔ 340

By similarity

Disulfide bond

336 ↔ 349

By similarity

Disulfide bond

351 ↔ 362

By similarity

Disulfide bond

369 ↔ 378

By similarity

Disulfide bond

374 ↔ 388

By similarity

Disulfide bond

390 ↔ 404

Disulfide bond

408 ↔ 413

Disulfide bond

417 ↔ 425

Disulfide bond

427 ↔ 439

Disulfide bond

445 ↔ 455

By similarity

Disulfide bond

451 ↔ 464

By similarity

Disulfide bond

466 ↔ 480

By similarity

Natural variations

Natural variant

43

1

A → T: dbSNP rs1800576. Ref.16 Ref.18

VAR_011368

Natural variant

79

1

G → A: dbSNP rs1800577. Ref.16

VAR_011369

Natural variant

162

1

A → P: dbSNP rs36110902.

VAR_049011

Natural variant

473

1

A → V: dbSNP rs1042579. Ref.20 Ref.5 Ref.7 Ref.17 Ref.19

VAR_011370

Natural variant

486

1

D → Y in THR-THBDD. Ref.15 Ref.16 Ref.20

VAR_011371

Natural variant

495

1

P → S: dbSNP rs1800578. Ref.16

VAR_011372

Natural variant

501

1

P → L: dbSNP rs1800579. Ref.16

VAR_011373

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

575

Helix Strand Turn

Details...

Helix

368 – 371

4

Beta strand

375 – 380

6

Beta strand

386 – 389

4

Beta strand

394 – 397

4

Beta strand

400 – 406

7

Beta strand

410 – 414

5

Beta strand

431 – 434

4

Turn

435 – 437

3

Beta strand

438 – 441

4

Helix

444 – 447

4

Beta strand

454 – 457

4

Beta strand

459 – 466

8

Beta strand

473 – 477

5

Sequences

	Sequence		Length	Mass (Da)
	P07204-1 [UniParc]. Last modified February 1, 1991. Version 2. Checksum: 9AF03CD151227D52	FASTA	575	60,329
	10 20 30 40 50 60 MLGVLVLGAL ALAGLGFPAP AEPQPGGSQC VEHDCFALYP GPATFLNASQ ICDGLRGHLM 70 80 90 100 110 120 TVRSSVAADV ISLLLNGDGG VGRRRLWIGL QLPPGCGDPK RLGPLRGFQW VTGDNNTSYS 130 140 150 160 170 180 RWARLDLNGA PLCGPLCVAV SAAEATVPSE PIWEEQQCEV KADGFLCEFH FPATCRPLAV 190 200 210 220 230 240 EPGAAAAAVS ITYGTPFAAR GADFQALPVG SSAAVAPLGL QLMCTAPPGA VQGHWAREAP 250 260 270 280 290 300 GAWDCSVENG GCEHACNAIP GAPRCQCPAG AALQADGRSC TASATQSCND LCEHFCVPNP 310 320 330 340 350 360 DQPGSYSCMC ETGYRLAADQ HRCEDVDDCI LEPSPCPQRC VNTQGGFECH CYPNYDLVDG 370 380 390 400 410 420 ECVEPVDPCF RANCEYQCQP LNQTSYLCVC AEGFAPIPHE PHRCQMFCNQ TACPADCDPN 430 440 450 460 470 480 TQASCECPEG YILDDGFICT DIDECENGGF CSGVCHNLPG TFECICGPDS ALARHIGTDC 490 500 510 520 530 540 DSGKVDGGDS GSGEPPPSPT PGSTLTPPAV GLVHSGLLIG ISIASLCLVV ALLALLCHLR 550 560 570 KKQGAARAKM EYKCAAPSKE VVLQHVRTER TPQRL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation." Suzuki K., Kusumoto H., Deyashiki Y., Nishioka J., Maruyama I., Zushi M., Kawahara S., Honda G., Yamamoto S., Horiguchi S. EMBO J. 6:1891-1897(1987) [PubMed: 2820710] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 19-43.
[2]	"Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene." Wen D., Dittman W.A., Ye R.D., Deaven L.L., Majerus P.W., Sadler J.E. Biochemistry 26:4350-4357(1987) [PubMed: 2822087] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
[3]	"Human thrombomodulin gene is intron depleted: nucleic acid sequences of the cDNA and gene predict protein structure and suggest sites of regulatory control." Jackman R.W., Beeler D.L., Fritze L., Soff G., Rosenberg R.D. Proc. Natl. Acad. Sci. U.S.A. 84:6425-6429(1987) [PubMed: 2819876] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C." Shirai T., Shiojiri S., Ito H., Yamamoto S., Kusumoto H., Deyashiki Y., Maruyama I., Suzuki K. J. Biochem. 103:281-285(1988) [PubMed: 2836377] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	SeattleSNPs variation discovery resource Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT VAL-473.
[6]	"The DNA sequence and comparative analysis of human chromosome 20." Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J. Nature 414:865-871(2001) [PubMed: 11780052] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT VAL-473. Tissue: Brain and Lung.
[8]	"Identification of the predominant glycosaminoglycan-attachment site in soluble recombinant human thrombomodulin: potential regulation of functionality by glycosyltransferase competition for serine 474." Gerlitz B., Hassell T., Vlahos C.J., Parkinson J.F., Bang N.U., Grinnell B.W. Biochem. J. 295:131-140(1993) [PubMed: 8216207] [Abstract] Cited for: GLYCOSYLATION AT SER-492, MUTAGENESIS.
[9]	"Urinary thrombomodulin, its isolation and characterization." Yamamoto S., Mizoguchi T., Tamaki T., Ohkuchi M., Kimura S., Aoki N. J. Biochem. 113:433-440(1993) [PubMed: 8390446] [Abstract] Cited for: HYDROXYLATION AT ASN-342.
[10]	"The structure of a 19-residue fragment from the C-loop of the fourth epidermal growth factor-like domain of thrombomodulin." Adler M., Seto M.H., Nitecki D.E., Lin J.H., Light D.R., Morser J. J. Biol. Chem. 270:23366-23372(1995) [PubMed: 7559494] [Abstract] Cited for: STRUCTURE BY NMR OF 389-407.
[11]	"Synthesis, activity, and preliminary structure of the fourth EGF-like domain of thrombomodulin." Meininger D.P., Hunter M.J., Komives E.A. Protein Sci. 4:1683-1695(1995) [PubMed: 8528067] [Abstract] Cited for: STRUCTURE BY NMR OF 364-407.
[12]	"Thrombin-bound structure of an EGF subdomain from human thrombomodulin determined by transferred nuclear Overhauser effects." Srinivasan J., Hu S., Hrabal R., Zhu Y., Komives E.A., Ni F. Biochemistry 33:13553-13560(1994) [PubMed: 7947766] [Abstract] Cited for: STRUCTURE BY NMR OF 427-444.
[13]	"Structural resiliency of an EGF-like subdomain bound to its target protein, thrombin." Hrabal R., Komives E.A., Ni F. Protein Sci. 5:195-203(1996) [PubMed: 8745396] [Abstract] Cited for: STRUCTURE BY NMR OF 427-444.
[14]	"Structure of the fifth EGF-like domain of thrombomodulin: an EGF-like domain with a novel disulfide-bonding pattern." Sampoli Benitez B.A., Hunter M.J., Meininger D.P., Komives E.A. J. Mol. Biol. 273:913-926(1997) [PubMed: 9367781] [Abstract] Cited for: STRUCTURE BY NMR OF 405-444.
[15]	"The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease." Oehlin A.-K., Marlar R.A. Blood 85:330-336(1995) [PubMed: 7811989] [Abstract] Cited for: VARIANT THR-THBDD TYR-486.
[16]	"Thrombomodulin gene variations and thromboembolic disease." Oehlin A.-K., Norlund L., Marlar R.A. Thromb. Haemost. 78:396-400(1997) [PubMed: 9198186] [Abstract] Cited for: VARIANT THR-THBDD TYR-486, VARIANTS THR-43; ALA-79; SER-495 AND LEU-501.
[17]	"A common thrombomodulin amino acid dimorphism is associated with myocardial infarction." Norlund L., Holm J., Zoller B., Oehlin A.-K. Thromb. Haemost. 77:248-251(1997) [PubMed: 9157575] [Abstract] Cited for: VARIANT VAL-473.
[18]	"A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men." Doggen C.J.M., Kunz G., Rosendaal F.R., Lane D.A., Vos H.L., Stubbs P.J., Manger Cats V., Ireland H. Thromb. Haemost. 80:743-748(1998) [PubMed: 9843165] [Abstract] Cited for: VARIANT THR-43.
[19]	"Thrombomodulin Ala455Val polymorphism and risk of coronary heart disease." Wu K.K., Aleksic N., Ahn C., Boerwinkle E., Folsom A.R., Juneja H. Circulation 103:1386-1389(2001) [PubMed: 11245641] [Abstract] Cited for: VARIANT VAL-473.
[20]	"Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia." Faioni E.M., Franchi F., Castaman G., Biguzzi E., Rodeghiero F. Br. J. Haematol. 118:595-599(2002) [PubMed: 12139752] [Abstract] Cited for: VARIANT THR-THBDD TYR-486, VARIANT VAL-473.
+	Additional computationally mapped references.

Web resources

Wikipedia

Thrombomodulin entry

SeattleSNPs

Functional Glycomics Gateway - Glycan Binding

Thrombomodulin

Cross-references

Sequence databases

EMBLGenBankDDBJ

X05495 mRNA. Translation: CAA29045.1.
M16552 mRNA. Translation: AAB59508.1.
J02973 Genomic DNA. Translation: AAA61175.1.
D00210 Genomic DNA. Translation: BAA00149.1.
AF495471 Genomic DNA. Translation: AAM03232.1.
AL049651 Genomic DNA. Translation: CAB51954.1.
BC035602 mRNA. Translation: AAH35602.2.
BC053357 mRNA. Translation: AAH53357.1.

IPI

IPI00010737.

PIR

THHUB. A41442.

RefSeq

NP_000352.1.

UniGene

Hs.2030

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1ADX	NMR	-	A	405-444	[»]
1DQB	NMR	-	A	364-444	[»]
1DX5	X-ray	2.30	I/J/K/L	363-480	[»]
1EGT	NMR	-	A	427-437	[»]
1FGD	NMR	-	A	427-444	[»]
1FGE	NMR	-	A	425-444	[»]
1HLT	X-ray	3.00	R	426-444	[»]
1TMR	NMR	-	A	389-405	[»]
1ZAQ	NMR	-	A	364-407	[»]
2ADX	NMR	-	A	405-444	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P07204. 1 interaction.

PTM databases

GlycoSuiteDB

P07204.

Proteomic databases

PRIDE

P07204.

Genome annotation databases

Ensembl

ENSG00000178726. Homo sapiens. [Contig view]

GeneID

7056.

KEGG

hsa:7056.

NMPDR

fig|9606.3.peg.19969.

Organism-specific databases

GeneCards

GC20M022974.

H-InvDB

HIX0015686.

HGNC

HGNC:11784. THBD.

HPA

CAB002425.
HPA002982.

MIM

188040. gene+phenotype.

Orphanet

3324. Thrombomodulin anomalies, familial.

PharmGKB

PA36496.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P07204.

HOVERGEN

P07204.

OMA

P07204. ADFQALP.

Enzyme and pathway databases

Reactome

REACT_604. Hemostasis.
REACT_6900. Signaling in Immune system.

Gene expression databases

ArrayExpress

P07204.

Bgee

P07204.

CleanEx

HS_THBD.

GermOnline

ENSG00000178726. Homo sapiens.

Family and domain databases

InterPro

IPR001304. C-type_lectin.
IPR016186. C-type_lectin-like.
IPR016316. CD93/CD141.
IPR006209. EGF.
IPR006210. EGF-like.
IPR013032. EGF-like_reg_CS.
IPR000152. EGF-type_Asp/Asn_hydroxyl_CS.
IPR000742. EGF_3.
IPR001881. EGF_Ca_bd.
IPR013091. EGF_Ca_bd_2.
IPR018097. EGF_Ca_bd_CS.
IPR015149. Tme5_EGF-like.
[Graphical view]

Gene3D

G3DSA:3.10.100.10. C-type_lectin-like. 1 hit.

Pfam

PF00008. EGF. 2 hits.
PF07645. EGF_CA. 2 hits.
PF00059. Lectin_C. 1 hit.
PF09064. Tme5_EGF_like. 1 hit.
[Graphical view]

PIRSF

PIRSF001775. CD93/CD141. 1 hit.

SMART

SM00034. CLECT. 1 hit.
SM00181. EGF. 5 hits.
SM00179. EGF_CA. 1 hit.
[Graphical view]

PROSITE

PS00010. ASX_HYDROXYL. 2 hits.
PS50041. C_TYPE_LECTIN_2. 1 hit.
PS00022. EGF_1. False negative.
PS01186. EGF_2. 2 hits.
PS50026. EGF_3. 4 hits.
PS01187. EGF_CA. 2 hits.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00055. Drotrecogin alfa.

NextBio

27593.

SOURCE

Search...

Entry information

Entry name

TRBM_HUMAN

Accession

Primary (citable) accession number: P07204
Secondary accession number(s): Q8IV29, Q9UC32

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1988
Last sequence update:	February 1, 1991
Last modified:	June 16, 2009
This is version 137 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)