Reviewed, UniProtKB/Swiss-Prot P00734 (THRB_HUMAN)

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- Recommended name:
            Activation peptide fragment 1
    2- Recommended name:
            Activation peptide fragment 2
    3- Recommended name:
            Thrombin light chain
    4- Recommended name:
            Thrombin heavy chain

Gene names

Name:

F2

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	622 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.
Catalytic activity	Selective cleavage of Arg-|-Gly bonds in fibrinogen to form fibrin and release fibrinopeptides A and B.
Subcellular location	Secreted › extracellular space.
Tissue specificity	Expressed by the liver and secreted in plasma.
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.
Involvement in disease	Defects in F2 are the cause of various forms of dysprothrombinemia [MIM:176930]. Genetic variations in F2 may be a cause of susceptibility to ischemic stroke [MIM:601367]; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors.
Pharmaceutical use	The peptide TP508 also known as Chrysalin (Orthologic) could be used to accelerate repair of both soft and hard tissues.
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. It is not known whether 1 or 2 smaller activation peptides, with additional cleavage after Arg-314, are released in natural blood clotting. Thrombin can itself cleave the N-terminal fragment (fragment 1) of the prothrombin, prior to its activation by factor Xa. The cleavage after Arg-198, observed in vitro, does not occur in plasma.
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
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Kringle Repeat Signal
Ligand	Calcium
Molecular function	Hydrolase Protease Serine protease
PTM	Cleavage on pair of basic residues Gamma-carboxyglutamic acid Glycoprotein Zymogen
Technical term	3D-structure Direct protein sequencing Pharmaceutical
Gene Ontology (GO)
Uncategorized	thrombin activity Inferred from direct assay. Source: UniProtKB
Biological process	STAT protein nuclear translocation Traceable author statement. Source: ProtInc acute-phase response Inferred from electronic annotation. Source: UniProtKB-KW caspase activation Traceable author statement. Source: ProtInc cell surface receptor linked signal transduction Inferred from direct assay. Source: UniProtKB fibrinolysis Inferred from direct assay. Source: UniProtKB multicellular organismal development Traceable author statement. Source: ProtInc platelet activation Traceable author statement. Source: UniProtKB positive regulation of blood coagulation Inferred from direct assay. Source: UniProtKB positive regulation of collagen biosynthetic process Inferred from direct assay. Source: UniProtKB proteolysis Traceable author statement. Source: ProtInc release of sequestered calcium ion into cytosol Inferred from direct assay. Source: UniProtKB tyrosine phosphorylation of STAT protein Traceable author statement. Source: ProtInc
Cellular component	extracellular space Ref.27 Traceable author statement. Source: ProtInc plasma membrane Inferred from Experiment. Source: Reactome soluble fraction Ref.28 Traceable author statement. Source: ProtInc
Molecular function	calcium ion binding Inferred from electronic annotation. Source: InterPro receptor binding Inferred from physical interaction. Source: UniProtKB serine-type endopeptidase activity Inferred from direct assay. Source: UniProtKB thrombospondin receptor activity Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
	Q846V4	3	EBI-297094,EBI-989571	From a different organism.
THBD	P07204	1	EBI-297094,EBI-941422

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_0000028159

Chain

44 – 622

579

Prothrombin

PRO_0000028160

Peptide

44 – 198

155

Activation peptide fragment 1

PRO_0000028161

Peptide

199 – 327

129

Activation peptide fragment 2

PRO_0000028162

Chain

328 – 363

36

Thrombin light chain

PRO_0000028163

Chain

364 – 622

259

Thrombin heavy chain

PRO_0000028164

Regions

Domain

44 – 89

46

Gla

Domain

108 – 186

79

Kringle 1

Domain

213 – 291

79

Kringle 2

Domain

364 – 618

255

Peptidase S1

Region

551 – 573

23

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

Sites

Active site

406

1

Charge relay system

Active site

462

1

Charge relay system

Active site

568

1

Charge relay system

Site

198 – 199

2

Cleavage; by thrombin

Site

327 – 328

2

Cleavage; by factor Xa

Site

363 – 364

2

Cleavage; by factor Xa

Amino acid modifications

Modified residue

49

1

4-carboxyglutamate

Modified residue

50

1

4-carboxyglutamate

Modified residue

57

1

4-carboxyglutamate

Modified residue

59

1

4-carboxyglutamate

Modified residue

62

1

4-carboxyglutamate

Modified residue

63

1

4-carboxyglutamate

Modified residue

68

1

4-carboxyglutamate

Modified residue

69

1

4-carboxyglutamate

Modified residue

72

1

4-carboxyglutamate

Modified residue

75

1

4-carboxyglutamate

Glycosylation

121

1

N-linked (GlcNAc...)

Glycosylation

143

1

N-linked (GlcNAc...)

Glycosylation

416

1

N-linked (GlcNAc...)

Disulfide bond

60 ↔ 65

Disulfide bond

90 ↔ 103

Disulfide bond

108 ↔ 186

Disulfide bond

129 ↔ 169

Disulfide bond

157 ↔ 181

Disulfide bond

213 ↔ 291

Disulfide bond

234 ↔ 274

Disulfide bond

262 ↔ 286

Disulfide bond

336 ↔ 482

Interchain (between light and heavy chains)

Disulfide bond

391 ↔ 407

Disulfide bond

536 ↔ 550

By similarity

Disulfide bond

564 ↔ 594

By similarity

Natural variations

Natural variant

165

1

T → M: dbSNP rs5896.

VAR_011781

Natural variant

200

1

E → K in dysprothrombinemia; prothrombin type 3.

VAR_006711

Natural variant

314

1

R → C in dysprothrombinemia; Barcelona/Madrid.

VAR_006712

Natural variant

314

1

R → H in dysprothrombinemia; Padua-1.

VAR_006713

Natural variant

380

1

M → T in dysprothrombinemia; Himi-1.

VAR_006714

Natural variant

386

1

P → T: dbSNP rs5897.

VAR_011782

Natural variant

425

1

R → C in dysprothrombinemia; Quick-1.

VAR_006715

Natural variant

431

1

R → H in dysprothrombinemia; Himi-2.

VAR_006716

Natural variant

461

1

R → W in dysprothrombinemia; Tokushima.

VAR_006717

Natural variant

509

1

E → A in dysprothrombinemia; Salakta/Frankfurt.

VAR_006718

Natural variant

601

1

G → V in dysprothrombinemia; Quick-2.

VAR_006719

Experimental info

Sequence conflict

119

1

H → N AA sequence Ref.4

Sequence conflict

121

1

N → S AA sequence Ref.4

Sequence conflict

164

1

T → I AA sequence Ref.4

Sequence conflict

164

1

T → N in CAA23842. Ref.3

Sequence conflict

176

1

V → A AA sequence Ref.4

Sequence conflict

183

1

I → T AA sequence Ref.4

Sequence conflict

194 – 195

2

AM → MV AA sequence Ref.4

Sequence conflict

308

1

D → DEE AA sequence Ref.4

Sequence conflict

335

1

D → N AA sequence Ref.5

Sequence conflict

349

1

D → N AA sequence Ref.5

Sequence conflict

369

1

D → N AA sequence Ref.5

Sequence conflict

398

1

D → N AA sequence Ref.5

Sequence conflict

414

1

D → N AA sequence Ref.5

Sequence conflict

485

1

D → N AA sequence Ref.5

Sequence conflict

494

1

Q → G AA sequence Ref.5

Sequence conflict

504

1

W → Y AA sequence Ref.5

Sequence conflict

509

1

E → S AA sequence Ref.5

Sequence conflict

511

1

W → V AA sequence Ref.5

Sequence conflict

514

1

N → D AA sequence Ref.5

Sequence conflict

529 – 530

2

PI → AL AA sequence Ref.5

Sequence conflict

532

1

E → Q AA sequence Ref.5

Secondary structure

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622

Helix Strand Turn

Details...

Turn

334 – 337

4

Turn

340 – 342

3

Helix

343 – 345

3

Helix

352 &nd