P19221 (THRB_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Prothrombin
EC=3.4.21.5

Alternative name(s):
Coagulation factor II

Cleaved into the following 4 chains:

1. Activation peptide fragment 1
2. Activation peptide fragment 2
3. Thrombin light chain
4. Thrombin heavy chain

Gene names

Name:	F2
Synonyms:	Cf2

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	618 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	Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing By similarity.
Catalytic activity	Selective cleavage of Arg-|-Gly bonds in fibrinogen to form fibrin and release fibrinopeptides A and B.
Enzyme regulation	Inhibited by SERPINA5 By similarity.
Subunit structure	Heterodimer (named alpha-thrombin) of a light and a heavy chain; disulfide-linked. Forms a heterodimer with SERPINA5 By similarity. Ref.5
Post-translational modification	The gamma-carboxyglutamyl residues, which bind calcium ions, result from the carboxylation of glutamyl residues by a microsomal enzyme, the vitamin K-dependent carboxylase. The modified residues are necessary for the calcium-dependent interaction with a negatively charged phospholipid surface, which is essential for the conversion of prothrombin to thrombin.
Miscellaneous	Prothrombin is activated on the surface of a phospholipid membrane that binds the amino end of prothrombin and factors Va and Xa in Ca-dependent interactions; factor Xa removes the activation peptide and cleaves the remaining part into light and heavy chains. The activation process starts slowly because factor V itself has to be activated by the initial, small amounts of thrombin. Thrombin can itself cleave the N-terminal fragment (fragment 1) of the prothrombin, prior to its activation by factor Xa.
Sequence similarities	Belongs to the peptidase S1 family. Contains 1 Gla (gamma-carboxy-glutamate) domain. Contains 2 kringle domains. Contains 1 peptidase S1 domain.

Ontologies

Keywords
Biological process	Acute phase Blood coagulation Hemostasis
Domain	Kringle Repeat Signal
Ligand	Calcium
Molecular function	Hydrolase Protease Serine protease
PTM	Cleavage on pair of basic residues Disulfide bond Gamma-carboxyglutamic acid Glycoprotein Zymogen
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	acute-phase response Inferred from electronic annotation. Source: UniProtKB-KW cytosolic calcium ion homeostasis Inferred from electronic annotation. Source: Compara fibrinolysis Inferred from electronic annotation. Source: Compara negative regulation of astrocyte differentiation Inferred from electronic annotation. Source: Compara negative regulation of proteolysis Inferred from electronic annotation. Source: Compara platelet activation Inferred from direct assay PubMed 17380206. Source: MGI positive regulation of blood coagulation Inferred from electronic annotation. Source: Compara positive regulation of cell growth Inferred from genetic interaction PubMed 18398001. Source: MGI positive regulation of cell proliferation Inferred from genetic interaction PubMed 18398001. Source: MGI positive regulation of collagen biosynthetic process Inferred from electronic annotation. Source: Compara positive regulation of phosphatidylinositol 3-kinase cascade Inferred from genetic interaction PubMed 18398001. Source: MGI positive regulation of phospholipase C-activating G-protein coupled receptor signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of protein phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of reactive oxygen species metabolic process Inferred from electronic annotation. Source: Compara positive regulation of release of sequestered calcium ion into cytosol Inferred from electronic annotation. Source: Compara proteolysis Inferred from electronic annotation. Source: UniProtKB-KW regulation of cell shape Inferred from genetic interaction PubMed 18398001. Source: MGI regulation of gene expression Inferred from direct assay PubMed 16720835. Source: MGI thrombin receptor signaling pathway Inferred from sequence orthology PubMed 18398001. Source: MGI
Cellular_component	extracellular space Inferred from electronic annotation. Source: Compara
Molecular_function	calcium ion binding Inferred from electronic annotation. Source: InterPro serine-type endopeptidase activity Inferred from direct assay PubMed 18398001. Source: MGI thrombospondin receptor activity Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 24

24

Potential

Propeptide

25 – 43

19

PRO_0000028165

Chain

44 – 618

575

Prothrombin

PRO_0000028166

Peptide

44 – 200

157

Activation peptide fragment 1

PRO_0000028167

Peptide

201 – 324

124

Activation peptide fragment 2

PRO_0000028168

Chain

325 – 360

36

Thrombin light chain

PRO_0000028169

Chain

361 – 618

258

Thrombin heavy chain

PRO_0000028170

Regions

Domain

44 – 90

47

Gla

Domain

109 – 187

79

Kringle 1

Domain

215 – 292

78

Kringle 2

Domain

361 – 615

255

Peptidase S1

Region

548 – 570

23

High affinity receptor-binding region which is also known as the TP508 peptide By similarity

Sites

Active site

403

1

Charge relay system By similarity

Active site

459

1

Charge relay system By similarity

Active site

565

1

Charge relay system By similarity

Site

200 – 201

2

Cleavage; by thrombin

Site

324 – 325

2

Cleavage; by factor Xa

Site

360 – 361

2

Cleavage; by factor Xa

Amino acid modifications

Modified residue

50

1

4-carboxyglutamate

Modified residue

51

1

4-carboxyglutamate

Modified residue

58

1

4-carboxyglutamate

Modified residue

60

1

4-carboxyglutamate

Modified residue

63

1

4-carboxyglutamate

Modified residue

64

1

4-carboxyglutamate

Modified residue

69

1

4-carboxyglutamate

Modified residue

70

1

4-carboxyglutamate

Modified residue

73

1

4-carboxyglutamate

Modified residue

76

1

4-carboxyglutamate

Glycosylation

122

1

N-linked (GlcNAc...) Ref.4

Glycosylation

144

1

N-linked (GlcNAc...)

Glycosylation

413

1

N-linked (GlcNAc...) Ref.4

Glycosylation

553

1

N-linked (GlcNAc...) Ref.4

Disulfide bond

61 ↔ 66

By similarity

Disulfide bond

91 ↔ 104

By similarity

Disulfide bond

109 ↔ 187

By similarity

Disulfide bond

130 ↔ 170

By similarity

Disulfide bond

158 ↔ 182

By similarity

Disulfide bond

215 ↔ 293

By similarity

Disulfide bond

236 ↔ 276

By similarity

Disulfide bond

264 ↔ 288

By similarity

Disulfide bond

333 ↔ 479

Interchain (between light and heavy chains) By similarity

Disulfide bond

388 ↔ 404

Ref.5

Disulfide bond

533 ↔ 547

Ref.5

Disulfide bond

561 ↔ 591

Ref.5

Experimental info

Mutagenesis

565

1

S → A: Loss of protease activity. Ref.6

Secondary structure

1

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618

Helix Strand Turn

Details...

Helix

323 – 326

4

Turn

330 – 334

5

Turn

337 – 339

3

Helix

340 – 342

3

Helix

349 – 355

7

Beta strand

375 – 380

6

Turn

381 – 384

4

Beta strand

385 – 400

16

Helix

402 – 405

4

Helix

408 – 410

3

Turn

416 – 418

3

Beta strand

419 – 424

6

Beta strand

437 – 439

3

Beta strand

441 – 446

6

Turn

452 – 455

4

Beta strand

461 – 467

7

Helix

483 – 489

7

Beta strand

495 – 500

6

Beta strand

521 – 527

7

Helix

530 – 536

7

Beta strand

545 – 548

4

Turn

562 – 566

5

Beta strand

568 – 572

5

Turn

574 – 576

3

Beta strand

579 – 587

9

Beta strand

589 – 592

4

Beta strand

598 – 602

5

Helix

604 – 606

3

Helix

607 – 617

11

Sequences

	Sequence		Length	Mass (Da)
	P19221 [UniParc]. Last modified November 1, 1990. Version 1. Checksum: B89F719AAFD601E0	FASTA	618	70,269
	10 20 30 40 50 60 MSHVRGLGLP GCLALAALVS LVHSQHVFLA PQQALSLLQR VRRANSGFLE ELRKGNLERE 70 80 90 100 110 120 CVEEQCSYEE AFEALESPQD TDVFWAKYTV CDSVRKPRET FMDCLEGRCA MDLGVNYLGT 130 140 150 160 170 180 VNVTHTGIQC QLWRSRYPHK PEINSTTHPG ADLKENFCRN PDSSTTGPWC YTTDPTVRRE 190 200 210 220 230 240 ECSVPVCGQE GRTTVVMTPR SGGSKDNLSP PLGQCLTERG RLYQGNLAVT TLGSPCLPWN 250 260 270 280 290 300 SLPAKTLSKY QDFDPEVKLV ENFCRNPDWD EEGAWCYVAG QPGDFEYCNL NYCEEAVGEE 310 320 330 340 350 360 NYDVDESIAG RTTDAEFHTF FNEKTFGLGE ADCGLRPLFE KKSLKDTTEK ELLDSYIDGR 370 380 390 400 410 420 IVEGWDAEKG IAPWQVMLFR KSPQELLCGA SLISDRWVLT AAHCILYPPW DKNFTENDLL 430 440 450 460 470 480 VRIGKHSRTR YERNVEKISM LEKIYVHPRY NWRENLDRDI ALLKLKKPVP FSDYIHPVCL 490 500 510 520 530 540 PDKQTVTSLL RAGYKGRVTG WGNLRETWTT NINEIQPSVL QVVNLPIVER PVCKASTRIR 550 560 570 580 590 600 ITDNMFCAGF KVNDTKRGDA CEGDSGGPFV MKSPFNNRWY QMGIVSWGEG CDRKGKYGFY 610 THVFRLKRWI QKVIDQFG

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Characterization of the cDNA coding for mouse prothrombin and localization of the gene on mouse chromosome 2." Friezner Degen S.J., Schaffer L.A., Jamison C.S., Grant S.G., Fitzgibbon J.J., Pai J.-A., Chapman V.M., Elliott R.W. DNA Cell Biol. 9:487-498(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: C57BL/6. Tissue: Liver.
[2]	"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]. Strain: FVB/N. Tissue: Liver.
[3]	"Partial characterization of vertebrate prothrombin cDNAs: amplification and sequence analysis of the B chain of thrombin from nine different species." Banfield D.K., Macgillivray R.T. Proc. Natl. Acad. Sci. U.S.A. 89:2779-2783(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 384-618. Tissue: Liver.
[4]	"Enhanced analysis of the mouse plasma proteome using cysteine-containing tryptic glycopeptides." Bernhard O.K., Kapp E.A., Simpson R.J. J. Proteome Res. 6:987-995(2007) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-122; ASN-413 AND ASN-553, MASS SPECTROMETRY. Strain: C57BL/6. Tissue: Plasma.
[5]	"Structural basis of Na+ activation mimicry in murine thrombin." Marino F., Chen Z.-W., Ergenekan C.E., Bush-Pelc L.A., Mathews F.S., Di Cera E. J. Biol. Chem. 282:16355-16361(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 319-618, DISULFIDE BONDS.
[6]	"Crystal structures of murine thrombin in complex with the extracellular fragments of murine protease-activated receptors PAR3 and PAR4." Bah A., Chen Z.-W., Bush-Pelc L.A., Mathews F.S., Di Cera E. Proc. Natl. Acad. Sci. U.S.A. 104:11603-11608(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 317-618 OF MUTANT ALA-565 IN COMPLEXES WITH PAR3/F2RL2 AND PAR4/F2RL3, MUTAGENESIS OF SER-565.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X52308 mRNA. Translation: CAA36548.1.
BC013662 mRNA. Translation: AAH13662.1.
M81394 mRNA. Translation: AAA40435.1.

IPI

IPI00114206.

PIR

A35827.

RefSeq

NP_034298.1. NM_010168.2.

UniGene

Mm.89048.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2OCV	X-ray	2.20	A	319-360	[»]
			B	361-618	[»]
2PUX	X-ray	2.00	A	317-360	[»]
			B	361-618	[»]
2PV9	X-ray	3.50	A	317-360	[»]
			B	361-618	[»]
3EDX	X-ray	2.40	A/C/E	317-360	[»]
			B/D/F	361-618	[»]
3HK3	X-ray	1.94	A	317-360	[»]
			B	361-618	[»]
3HK6	X-ray	3.20	A/C	317-360	[»]
			B/D	361-618	[»]
3HKI	X-ray	2.20	A/D	317-360	[»]
			B/E	361-618	[»]

ProteinModelPortal

P19221.

SMR

P19221. Positions 44-200, 214-618.

ModBase

Search...

Protein-protein interaction databases

MINT

MINT-4137721.

STRING

10090.ENSMUSP00000028681.

Protein family/group databases

MEROPS

S01.217.

PTM databases

PhosphoSite

P19221.

Proteomic databases

PaxDb

P19221.

PRIDE

P19221.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000028681; ENSMUSP00000028681; ENSMUSG00000027249.

GeneID

14061.

KEGG

mmu:14061.

UCSC

uc008kwg.1. mouse.

Organism-specific databases

CTD

2147.

MGI

MGI:88380. F2.

Phylogenomic databases

eggNOG

COG5640.

HOGENOM

HOG000251824.

HOVERGEN

HBG108381.

InParanoid

P19221.

KO

K01313.

OMA

ECQLWRS.

Gene expression databases

ArrayExpress

P19221.

Bgee

P19221.

CleanEx

MM_F2.

Genevestigator

P19221.

GermOnline

ENSMUSG00000027249. Mus musculus.

Family and domain databases

Gene3D

2.40.20.10. 2 hits.
4.10.140.10. 1 hit.
4.10.740.10. 1 hit.

InterPro

IPR017857. Coagulation_fac_subgr_Gla_dom.
IPR000294. GLA_domain.
IPR000001. Kringle.
IPR013806. Kringle-like.
IPR018056. Kringle_CS.
IPR001254. Peptidase_S1.
IPR018114. Peptidase_S1_AS.
IPR001314. Peptidase_S1A.
IPR003966. Prothrombin/thrombin.
IPR018992. Thrombin_light_chain.
IPR009003. Trypsin-like_Pept_dom.
[Graphical view]

Pfam

PF00594. Gla. 1 hit.
PF00051. Kringle. 2 hits.
PF09396. Thrombin_light. 1 hit.
PF00089. Trypsin. 1 hit.
[Graphical view]

PIRSF

PIRSF001149. Thrombin. 1 hit.

PRINTS

PR00722. CHYMOTRYPSIN.
PR00001. GLABLOOD.
PR01505. PROTHROMBIN.

SMART

SM00069. GLA. 1 hit.
SM00130. KR. 2 hits.
SM00020. Tryp_SPc. 1 hit.
[Graphical view]

SUPFAM

SSF57440. Kringle-like. 2 hits.
SSF50494. Pept_Ser_Cys. 1 hit.
SSF57630. VitK_dep_GLA. 1 hit.

PROSITE

PS00011. GLA_1. 1 hit.
PS50998. GLA_2. 1 hit.
PS00021. KRINGLE_1. 2 hits.
PS50070. KRINGLE_2. 2 hits.
PS50240. TRYPSIN_DOM. 1 hit.
PS00134. TRYPSIN_HIS. 1 hit.
PS00135. TRYPSIN_SER. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChEMBL

CHEMBL1075308.

ChiTaRS

F2. mouse.

EvolutionaryTrace

P19221.

NextBio

285028.

PMAP-CutDB

P19221.

SOURCE

Search...

Entry information

Entry name

THRB_MOUSE

Accession

Primary (citable) accession number: P19221

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1990
Last sequence update:	November 1, 1990
Last modified:	May 29, 2013
This is version 145 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program