Reviewed, UniProtKB/Swiss-Prot P00735 (THRB_BOVIN)

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

Bos taurus (Bovine)

Taxonomic identifier

9913 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Laurasiatheria › Cetartiodactyla › Ruminantia › Pecora › Bovidae › Bovinae › Bos

Protein attributes

Sequence length	625 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.
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.
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
Cellular component	Secreted
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 Direct protein sequencing
Gene Ontology (GO)
Biological process	acute-phase response Inferred from electronic annotation. Source: UniProtKB-KW blood coagulation Inferred from electronic annotation. Source: UniProtKB-KW proteolysis Inferred from electronic annotation. Source: InterPro
Cellular component	extracellular space Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	calcium ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from physical interaction. Source: IntAct serine-type endopeptidase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
coa	Q4W8J9	2	EBI-990806,EBI-990838	From a different organism.

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

Ref.4

PRO_0000028153

Chain

44 – 625

582

Prothrombin

PRO_0000028154

Peptide

44 – 199

156

Activation peptide fragment 1

PRO_0000028155

Peptide

200 – 317

118

Activation peptide fragment 2

PRO_0000028156

Chain

318 – 366

49

Thrombin light chain

PRO_0000028157

Chain

367 – 625

259

Thrombin heavy chain

PRO_0000028158

Regions

Domain

44 – 90

47

Gla

Domain

109 – 187

79

Kringle 1

Domain

214 – 292

79

Kringle 2

Domain

367 – 621

255

Peptidase S1

Region

554 – 576

23

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

Sites

Active site

409

1

Charge relay system

Active site

465

1

Charge relay system

Active site

571

1

Charge relay system

Site

199 – 200

2

Cleavage; by thrombin

Site

317 – 318

2

Cleavage; by factor Xa

Site

366 – 367

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

120

1

N-linked (GlcNAc...) Ref.4 Ref.8

Glycosylation

144

1

N-linked (GlcNAc...) Ref.4 Ref.8

Glycosylation

419

1

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

Disulfide bond

61 ↔ 66

Ref.4 Ref.8

Disulfide bond

91 ↔ 104

Ref.4 Ref.8

Disulfide bond

109 ↔ 187

Ref.4 Ref.8

Disulfide bond

130 ↔ 170

Ref.4 Ref.8

Disulfide bond

158 ↔ 182

Ref.4 Ref.8

Disulfide bond

214 ↔ 292

Ref.4 Ref.8

Disulfide bond

235 ↔ 275

Ref.4 Ref.8

Disulfide bond

263 ↔ 287

Ref.4 Ref.8

Disulfide bond

339 ↔ 485

Interchain (between light and heavy chains) Ref.4 Ref.8

Disulfide bond

394 ↔ 410

Ref.4 Ref.8

Disulfide bond

539 ↔ 553

Ref.4 Ref.8

Disulfide bond

567 ↔ 597

Ref.4 Ref.8

Natural variations

Natural variant

600

1

D → N

Experimental info

Sequence conflict

231

1

S → H in AAA30781. Ref.2

Sequence conflict

249

1

D → H in AAA30781. Ref.2

Sequence conflict

288

1

D → N AA sequence Ref.4

Sequence conflict

353

1

Q → E AA sequence Ref.4

Sequence conflict

355

1

E → Q AA sequence Ref.4

Sequence conflict

358

1

L → P in AAI05202. Ref.3

Sequence conflict

549 – 550

2

DN → ND AA sequence Ref.4

Secondary structure

1

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625

Helix Strand Turn

Details...

Beta strand

47 – 49

3

Helix

50 – 52

3

Helix

57 – 61

5

Helix

68 – 74

7

Helix

78 – 90

13

Turn

91 – 93

3

Helix

98 – 106

9

Beta strand

108 – 110

3

Beta strand

137 – 139

3

Turn

145 – 147

3

Beta strand

168 – 174

7

Beta strand

179 – 181

3

Beta strand

192 – 194

3

Helix

217 – 219

3

Beta strand

238 – 240

3

Helix

243 – 246

4

Beta strand

274 – 276

3

Beta strand

278 – 280

3

Beta strand

284 – 286

3

Beta strand

291 – 293

3

Beta strand

310 – 313

4

Beta strand

321 – 323

3

Turn

328 – 330

3

Turn

337 – 340

4

Turn

343 – 345

3

Helix

346 – 348

3

Helix

355 – 362

8

Beta strand

381 – 386

6

Turn

387 – 390

4

Beta strand

391 – 398

8

Beta strand

400 – 406

7

Helix

408 – 410

3

Helix

414 – 416

3

Turn

422 – 424

3

Beta strand

425 – 430

6

Beta strand

434 – 436

3

Helix

439 – 441

3

Beta strand

442 – 445

4

Beta strand

447 – 452

6

Turn

458 – 461

4

Beta strand

467 – 473

7

Helix

489 – 495

7

Beta strand

501 – 508

8

Beta strand

527 – 533

7

Helix

536 – 541

6

Beta strand

551 – 554

4

Helix

558 – 560

3

Beta strand

574 – 578

5

Turn

580 – 582

3

Beta strand

585 – 593

9

Beta strand

595 – 598

4

Beta strand

604 – 608

5

Turn

609 – 612

4

Helix

613 – 620

8

Sequences

	Sequence		Length	Mass (Da)
	P00735-1 [UniParc]. Last modified April 1, 1990. Version 2. Checksum: 95AFF17C23AD78F9	FASTA	625	70,506
	10 20 30 40 50 60 MARVRGPRLP GCLALAALFS LVHSQHVFLA HQQASSLLQR ARRANKGFLE EVRKGNLERE 70 80 90 100 110 120 CLEEPCSREE AFEALESLSA TDAFWAKYTA CESARNPREK LNECLEGNCA EGVGMNYRGN 130 140 150 160 170 180 VSVTRSGIEC QLWRSRYPHK PEINSTTHPG ADLRENFCRN PDGSITGPWC YTTSPTLRRE 190 200 210 220 230 240 ECSVPVCGQD RVTVEVIPRS GGSTTSQSPL LETCVPDRGR EYRGRLAVTT SGSRCLAWSS 250 260 270 280 290 300 EQAKALSKDQ DFNPAVPLAE NFCRNPDGDE EGAWCYVADQ PGDFEYCDLN YCEEPVDGDL 310 320 330 340 350 360 GDRLGEDPDP DAAIEGRTSE DHFQPFFNEK TFGAGEADCG LRPLFEKKQV QDQTEKELFE 370 380 390 400 410 420 SYIEGRIVEG QDAEVGLSPW QVMLFRKSPQ ELLCGASLIS DRWVLTAAHC LLYPPWDKNF 430 440 450 460 470 480 TVDDLLVRIG KHSRTRYERK VEKISMLDKI YIHPRYNWKE NLDRDIALLK LKRPIELSDY 490 500 510 520 530 540 IHPVCLPDKQ TAAKLLHAGF KGRVTGWGNR RETWTTSVAE VQPSVLQVVN LPLVERPVCK 550 560 570 580 590 600 ASTRIRITDN MFCAGYKPGE GKRGDACEGD SGGPFVMKSP YNNRWYQMGI VSWGEGCDRD 610 620 GKYGFYTHVF RLKKWIQKVI DRLGS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Structure and evolution of the bovine prothrombin gene." Irwin D.M., Robertson K.A., Macgillivray R.T.A. J. Mol. Biol. 200:31-45(1988) [PubMed: 3379642] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Characterization of bovine prothrombin mRNA and its translation product." McGillivray R.T.A., Davie E.W. Biochemistry 23:1626-1634(1984) [PubMed: 6326805] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	NIH - Mammalian Gene Collection (MGC) project Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: Hereford. Tissue: Fetal liver.
[4]	Magnusson S., Sottrup-Jensen L., Petersen T.E., Claeys H. (In) Hemker H.C., Veltkamp J.J. (eds.); Boerhaave symposium on prothrombin and related coagulation factors, pp.25-46, Leiden University Press, Leiden (1975) Cited for: PROTEIN SEQUENCE OF 44-625, DISULFIDE BONDS, GLYCOSYLATION AT ASN-120; ASN-144 AND ASN-419.
[5]	"Characterization of the bovine prothrombin gene." Irwin D.M., Ahern K.G., Pearson G.D., McGillivray R.T.A. Biochemistry 24:6854-6861(1985) [PubMed: 3000440] [Abstract] Cited for: GENE STRUCTURE.
[6]	"Three-dimensional structure of the kringle sequence: structure of prothrombin fragment 1." Park C.H., Tulinsky A. Biochemistry 25:3977-3982(1986) [PubMed: 3741841] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF ACTIVATION PEPTIDE 1.
[7]	"Structure of bovine prothrombin fragment 1 refined at 2.25-A resolution." Seshadri T.-P., Tulinsky A., Skrzypczak-Jankun E., Park C.H. J. Mol. Biol. 220:481-494(1991) [PubMed: 1856869] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF ACTIVATION PEPTIDE 1.
[8]	"The Ca2+ ion and membrane binding structure of the Gla domain of Ca-prothrombin fragment 1." Soriano-Garcia M., Padmanabhan K., de Vos A.M., Tulinsky A. Biochemistry 31:2554-2566(1992) [PubMed: 1547238] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF ACTIVATION PEPTIDE 1 IN COMPLEX WITH CALCIUM IONS, DISULFIDE BONDS, GLYCOSYLATION AT ASN-120 AND ASN-144.
[9]	"The structure of residues 7-16 of the A alpha-chain of human fibrinogen bound to bovine thrombin at 2.3-A resolution." Martin P.D., Robertson W., Turk D., Huber R., Bode W., Edwards B.F.P. J. Biol. Chem. 267:7911-7920(1992) [PubMed: 1560020] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) IN COMPLEX WITH FIBRINOGEN.
[10]	"The structure of a complex of bovine alpha-thrombin and recombinant hirudin at 2.8-A resolution." Vitali J., Martin P.D., Malkowski M.G., Robertson W.D., Lazar J.B., Winant R.C., Johnson P.H., Edwards B.F.P. J. Biol. Chem. 267:17670-17678(1992) [PubMed: 1517214] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 318-625 IN COMPLEX WITH HIRUDIN.
[11]	"Refined 2.3 A X-ray crystal structure of bovine thrombin complexes formed with the benzamidine and arginine-based thrombin inhibitors NAPAP, 4-TAPAP and MQPA. A starting point for improving antithrombotics." Brandstetter H., Turk D., Hoeffken H.W., Grosse D., Stuerzebecher J., Martin P.D., Edwards B.F.P., Bode W. J. Mol. Biol. 226:1085-1089(1992) [PubMed: 1518046] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
[12]	"The ornithodorin-thrombin crystal structure, a key to the TAP enigma?" van de Locht A., Stubbs M.T., Bode W., Friedrich T., Bollschweiler C., Hoffken W., Huber R. EMBO J. 15:6011-6017(1996) [PubMed: 8947023] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF COMPLEX WITH ORNITHODORIN.
[13]	"Structure of the thrombin complex with triabin, a lipocalin-like exosite-binding inhibitor derived from a triatomine bug." Fuentes-Prior P., Noeske-Jungblut C., Donner P., Schleuning W.-D., Huber R., Bode W. Proc. Natl. Acad. Sci. U.S.A. 94:11845-11850(1997) [PubMed: 9342325] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF COMPLEX WITH TRIABIN.
[14]	"Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins." Huang M., Rigby A.C., Morelli X., Grant M.A., Huang G., Furie B., Seaton B., Furie B.C. Nat. Struct. Biol. 10:751-756(2003) [PubMed: 12923575] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 44-190 IN COMPLEX WITH CALCIUM AND LYSOPHOSPHATIDYLSERINE.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

V00135 mRNA. Translation: CAA23451.1.
J00041 mRNA. Translation: AAA30781.1.
BC105201 mRNA. Translation: AAI05202.1.

IPI

IPI00710799.

PIR

TBBO. S02537.

RefSeq

NP_776302.1.

UniGene

Bt.29855

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1A0H	X-ray	3.20	A/D	208-366	[»]
			B/E	367-625	[»]
1AVG	X-ray	2.60	H	367-625	[»]
			L	326-366	[»]
1BBR	X-ray	2.30	E	517-625	[»]
			H	367-516	[»]
			J/L/M	318-366	[»]
			K/N	367-625	[»]
1ETR	X-ray	2.20	H	367-625	[»]
			L	318-366	[»]
1ETS	X-ray	2.30	H	367-625	[»]
			L	318-366	[»]
1ETT	X-ray	2.50	H	367-625	[»]
			L	318-366	[»]
1HRT	X-ray	2.80	H	367-625	[»]
			L	318-366	[»]
1ID5	X-ray	2.50	H	367-622	[»]
			L	318-366	[»]
1MKW	X-ray	2.30	H	367-625	[»]
			K	318-625	[»]
			L	318-366	[»]
1MKX	X-ray	2.20	H	367-625	[»]
			K	318-625	[»]
			L	318-366	[»]
1NL1	X-ray	1.90	A	44-190	[»]
1NL2	X-ray	2.30	A	44-189	[»]
1TBQ	X-ray	3.10	H/K	367-625	[»]
			J/L	318-366	[»]
1TBR	X-ray	2.60	H/K	367-625	[»]
			J/L	318-366	[»]
1TOC	X-ray	3.10	A/C/E/G	318-366	[»]
			B/D/F/H	367-625	[»]
1UCY	X-ray	2.20	E	517-625	[»]
			H	367-516	[»]
			J/L/M	318-366	[»]
			K/N	367-625	[»]
1UVT	X-ray	2.50	H	367-625	[»]
			L	318-366	[»]
1UVU	X-ray	2.80	H	367-625	[»]
			L	318-366	[»]
1VIT	X-ray	3.20	F	367-516	[»]
			G	517-625	[»]
			H	367-625	[»]
			L/M	318-366	[»]
1YCP	X-ray	2.50	H	367-625	[»]
			J/L	318-366	[»]
			K	367-516	[»]
			M	517-625	[»]
2A1D	X-ray	3.50	A/E	326-366	[»]
			B/F	367-625	[»]
2HPP	X-ray	3.30	P	214-292	[»]
2ODY	X-ray	2.35	A/C	318-366	[»]
			B/D	367-625	[»]
2PF1	X-ray	2.80	A	44-199	[»]
2PF2	X-ray	2.20	A	44-199	[»]
2SPT	X-ray	2.50	A	44-188	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:6099N.

IntAct

P00735. 1 interaction.

Protein family/group databases

MEROPS

S01.217.

Proteomic databases

PRIDE

P00735.

Genome annotation databases

Ensembl

ENSBTAG00000007148. Bos taurus. [Contig view]

GeneID

280685.

KEGG

bta:280685.

Phylogenomic databases

HOVERGEN

P00735.

OMA

P00735. EGNCAEG.

Enzyme and pathway databases

BRENDA

3.4.21.5. 251.

Family and domain databases

InterPro

IPR002383. Coagulation_factor_Gla.
IPR000294. GLA_domain.
IPR000001. Kringle.
IPR018056. Kringle_CS.
IPR018059. Kringle_sub.
IPR018114. Peptidase_S1/S6_AS.
IPR001254. Peptidase_S1_S6.
IPR001314. Peptidase_S1A.
IPR012051. Peptidase_S1A_pr.
IPR003966. Peptidase_S1A_prothrombin.
IPR018992. Thrombin_light_chain.
[Graphical view]

Gene3D

G3DSA:2.40.20.10. Kringle. 2 hits.
G3DSA:4.10.140.10. Thrombin_light_chain. 1 hit.

PANTHER

PTHR19355:SF61. Peptidase_S1A_pr. 1 hit.

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.
PR00018. KRINGLE.
PR01505. PROTHROMBIN.

ProDom

PD000395. Kringle. 2 hits.
[Graphical view] [Entries sharing at least one domain]

SMART

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

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 Resources

PMAP-CutDB

P00735.

Entry information

Entry name

THRB_BOVIN

Accession

Primary (citable) accession number: P00735
Secondary accession number(s): Q3MHK7

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	April 1, 1990
Last modified:	June 16, 2009
This is version 121 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)