P10646 (TFPI1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tissue factor pathway inhibitor
Short name=TFPI

Alternative name(s):
Extrinsic pathway inhibitor
Short name=EPI
Lipoprotein-associated coagulation inhibitor
Short name=LACI

Gene names

Name:	TFPI
Synonyms:	LACI, TFPI1

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	304 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	Inhibits factor X (X(a)) directly and, in a Xa-dependent way, inhibits VIIa/tissue factor activity, presumably by forming a quaternary Xa/LACI/VIIa/TF complex. It possesses an antithrombotic action and also the ability to associate with lipoproteins in plasma.
Subcellular location	Secreted.
Tissue specificity	Mostly in endothelial cells.
Domain	This inhibitor contains three inhibitory domains. The first domain interacts with VIIa and TF, the second one with Xa.
Post-translational modification	O-glycosylated. Ref.10 Ref.14 Ref.16
Sequence similarities	Contains 3 BPTI/Kunitz inhibitor domains.

Ontologies

Keywords
Biological process	Blood coagulation
Cellular component	Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Repeat Signal
Molecular function	Protease inhibitor Serine protease inhibitor
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	blood coagulation, extrinsic pathway Traceable author statement. Source: Reactome
Cellular component	extracellular space Inferred from direct assay. Source: BHF-UCL plasma membrane Traceable author statement. Source: Reactome
Molecular function	serine-type endopeptidase inhibitor activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

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

Isoform Alpha (identifier: P10646-1)

Also known as: TFPIalpha;

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 Beta (identifier: P10646-2)

Also known as: TFPIbeta;

The sequence of this isoform differs from the canonical sequence as follows:
     210-251: EFHGPSWCLT...CRPFKYSGCG → VTKEGTNDGW...LGLDSISCLC
     252-304: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 28

28

Ref.10 Ref.11 Ref.12

Chain

29 – 304

276

Tissue factor pathway inhibitor Ref.1

PRO_0000016871

Regions

Domain

54 – 104

51

BPTI/Kunitz inhibitor 1

Domain

125 – 175

51

BPTI/Kunitz inhibitor 2

Domain

217 – 267

51

BPTI/Kunitz inhibitor 3

Sites

Site

64 – 65

2

Reactive bond

Site

135 – 136

2

Reactive bond

Site

227 – 228

2

Reactive bond

Site

256

1

Not glycosylated

Amino acid modifications

Glycosylation

42

1

O-linked (GalNAc...); partial Ref.10

Glycosylation

145

1

N-linked (GlcNAc...) Ref.10 Ref.14 Ref.16

Glycosylation

195

1

N-linked (GlcNAc...) Ref.10 Ref.14

Glycosylation

202

1

O-linked (GalNAc...); partial Ref.10 Ref.14

Glycosylation

203

1

O-linked (GalNAc...) Ref.10 Ref.14

Disulfide bond

54 ↔ 104

By similarity

Disulfide bond

63 ↔ 87

By similarity

Disulfide bond

79 ↔ 100

By similarity

Disulfide bond

125 ↔ 175

Disulfide bond

134 ↔ 158

Disulfide bond

150 ↔ 171

Disulfide bond

217 ↔ 267

Disulfide bond

226 ↔ 250

Disulfide bond

242 ↔ 263

Natural variations

Alternative sequence

210 – 251

42

EFHGP…YSGCG → VTKEGTNDGWKNAAHIYQVF LNAFCIHASMFFLGLDSISC LC in isoform Beta.

VSP_003030

Alternative sequence

252 – 304

53

Missing in isoform Beta.

VSP_003031

Natural variant

292

1

V → M. Ref.20
Corresponds to variant rs5940 [ dbSNP | Ensembl ].

VAR_012004

Experimental info

Mutagenesis

64

1

K → I: Abolishes inhibition of VII(a)/TF.

Mutagenesis

135

1

R → L: Abolishes inhibition of X(a).

Mutagenesis

227

1

R → L: Abolishes inhibition of VII(a)/TF.

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

304

Helix Strand Turn

Details...

Helix

123 – 126

4

Beta strand

138 – 144

7

Turn

145 – 148

4

Beta strand

149 – 155

7

Beta strand

157 – 159

3

Beta strand

165 – 167

3

Helix

168 – 174

7

Turn

175 – 177

3

Beta strand

215 – 219

5

Beta strand

224 – 226

3

Beta strand

232 – 235

4

Turn

237 – 239

3

Beta strand

241 – 245

5

Beta strand

257 – 260

4

Helix

261 – 267

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform Alpha (TFPIalpha) [UniParc]. Last modified July 1, 1989. Version 1. Checksum: 5281E32B758B44FE	FASTA	304	35,015
	10 20 30 40 50 60 MIYTMKKVHA LWASVCLLLN LAPAPLNADS EEDEEHTIIT DTELPPLKLM HSFCAFKADD 70 80 90 100 110 120 GPCKAIMKRF FFNIFTRQCE EFIYGGCEGN QNRFESLEEC KKMCTRDNAN RIIKTTLQQE 130 140 150 160 170 180 KPDFCFLEED PGICRGYITR YFYNNQTKQC ERFKYGGCLG NMNNFETLEE CKNICEDGPN 190 200 210 220 230 240 GFQVDNYGTQ LNAVNNSLTP QSTKVPSLFE FHGPSWCLTP ADRGLCRANE NRFYYNSVIG 250 260 270 280 290 300 KCRPFKYSGC GGNENNFTSK QECLRACKKG FIQRISKGGL IKTKRKRKKQ RVKIAYEEIF VKNM
	Isoform Beta (TFPIbeta) [UniParc]. Checksum: 9B3F276A52B4F0B9	FASTA	251	28,653
	10 20 30 40 50 60 MIYTMKKVHA LWASVCLLLN LAPAPLNADS EEDEEHTIIT DTELPPLKLM HSFCAFKADD 70 80 90 100 110 120 GPCKAIMKRF FFNIFTRQCE EFIYGGCEGN QNRFESLEEC KKMCTRDNAN RIIKTTLQQE 130 140 150 160 170 180 KPDFCFLEED PGICRGYITR YFYNNQTKQC ERFKYGGCLG NMNNFETLEE CKNICEDGPN 190 200 210 220 230 240 GFQVDNYGTQ LNAVNNSLTP QSTKVPSLFV TKEGTNDGWK NAAHIYQVFL NAFCIHASMF 250 FLGLDSISCL C

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of a cDNA coding for the lipoprotein-associated coagulation inhibitor shows that it consists of three tandem Kunitz-type inhibitory domains." Wun T.-C., Kretzmer K.K., Girard T.J., Miletich J.P., Broze G.J. Jr. J. Biol. Chem. 263:6001-6004(1988) [PubMed: 2452157] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA).
[2]	"Identification of the 1.4 kb and 4.0 kb messages for the lipoprotein associated coagulation inhibitor and expression of the encoded protein." Girard T.J., Warren L.A., Novotny W.F., Bejcek B.E., Miletich J.P., Broze G.J. Jr. Thromb. Res. 55:37-50(1989) [PubMed: 2781520] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA).
[3]	"Intron-exon organization of the human gene coding for the lipoprotein-associated coagulation inhibitor: the factor Xa dependent inhibitor of the extrinsic pathway of coagulation." van der Logt C.P.E., Reitsma P.H., Bertina R.M. Biochemistry 30:1571-1577(1991) [PubMed: 1993173] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM ALPHA).
[4]	"Structure of the human lipoprotein-associated coagulation inhibitor gene. Intro/exon gene organization and localization of the gene to chromosome 2." Girard T.J., Eddy R., Wesselschmidt R.L., Macphail L.A., Likert K.M., Byers M.G., Shows T.B., Broze G.J. Jr. J. Biol. Chem. 266:5036-5041(1991) [PubMed: 2002045] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM ALPHA).
[5]	Chang J.-Y., Monroe D.M., Roberts H.R. Submitted (AUG-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM BETA).
[6]	SeattleSNPs variation discovery resource Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[7]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed: 15815621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	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 (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	"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] (ISOFORM BETA). Tissue: Pancreas.
[10]	"Biochemical characterization of plasma-derived tissue factor pathway inhibitor: post-translational modification of free, full-length form with particular reference to the sugar chain." Mori Y., Hamuro T., Nakashima T., Hamamoto T., Natsuka S., Hase S., Iwanaga S. J. Thromb. Haemost. 7:111-120(2009) [PubMed: 19017259] [Abstract] Cited for: PROTEIN SEQUENCE OF 29-304, MASS SPECTROMETRY, GLYCOSYLATION AT THR-42; ASN-145; ASN-195; SER-202 AND THR-203.
[11]	"Purification and characterization of the lipoprotein-associated coagulation inhibitor from human plasma." Novotny W.F., Girard T.J., Miletich J.P., Broze G.J. Jr. J. Biol. Chem. 264:18832-18837(1989) [PubMed: 2553722] [Abstract] Cited for: PROTEIN SEQUENCE OF 29-50.
[12]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed: 15340161] [Abstract] Cited for: PROTEIN SEQUENCE OF 29-43.
[13]	"Functional significance of the Kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor." Girard T.J., Warren L.A., Novotny W.F., Likert K.M., Brown S.G., Miletich J.P., Broze G.J. Jr. Nature 338:518-520(1989) [PubMed: 2927510] [Abstract] Cited for: INHIBITORY SITES.
[14]	"Amino acid sequence and carbohydrate structure of a recombinant human tissue factor pathway inhibitor expressed in Chinese hamster ovary cells: one N- and two O-linked carbohydrate chains are located between Kunitz domains 2 and 3 and one N-linked carbohydrate chain is in Kunitz domain 2." Nakahara Y., Miyata T., Hamuro T., Funatsu A., Miyagi M., Tsunasawa S., Kato H. Biochemistry 35:6450-6459(1996) [PubMed: 8639592] [Abstract] Cited for: GLYCOSYLATION AT ASN-145; ASN-195; SER-202 AND THR-203.
[15]	"Regulation of coagulation by a multivalent Kunitz-type inhibitor." Broze G.J. Jr., Girard T.J., Novotny W.F. Biochemistry 29:7539-7546(1990) [PubMed: 2271516] [Abstract] Cited for: REVIEW.
[16]	"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry." Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., Smith R.D. J. Proteome Res. 4:2070-2080(2005) [PubMed: 16335952] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-145, MASS SPECTROMETRY. Tissue: Plasma.
[17]	"The three-dimensional structure of recombinant leech-derived tryptase inhibitor in complex with trypsin. Implications for the structure of human mast cell tryptase and its inhibition." Stubbs M.T., Morenweiser R., Stuerzebecher J., Bauer M., Bode W., Huber R., Piechottka G.P., Matschiner G., Sommerhoff C.P., Fritz H., Auerswald E.A. J. Biol. Chem. 272:19931-19937(1997) [PubMed: 9242660] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 121-178 IN COMPLEX WITH TRYPSIN.
[18]	"The second Kunitz domain of human tissue factor pathway inhibitor: cloning, structure determination and interaction with factor Xa." Burgering M.J.M., Orbons L.P.M., van der Doelen A., Mulders J., Theunissen H.J.M., Grootenhuis P.D.J., Bode W., Huber R., Stubbs M.T. J. Mol. Biol. 269:395-407(1997) [PubMed: 9199408] [Abstract] Cited for: STRUCTURE BY NMR OF 121-182.
[19]	"Structural mechanism for heparin-binding of the third Kunitz domain of human tissue factor pathway inhibitor." Mine S., Yamazaki T., Miyata T., Hara S., Kato H. Biochemistry 41:78-85(2002) [PubMed: 11772005] [Abstract] Cited for: STRUCTURE BY NMR OF 210-270.
[20]	"Characterization of single-nucleotide polymorphisms in coding regions of human genes." Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S. Nat. Genet. 22:231-238(1999) [PubMed: 10391209] [Abstract] Cited for: VARIANT MET-292.
[21]	Erratum Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S. Nat. Genet. 23:373-373(1999)
+	Additional computationally mapped references.

Web resources

Wikipedia

TFPI entry

SeattleSNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

J03225 mRNA. Translation: AAA52022.1.
M58650 , M58644, M58645, M58646, M58647, M58648, M58649 Genomic DNA. Translation: AAA59480.1.
M59499 , M59493, M59494, M59495, M59496, M59497, M59498 Genomic DNA. Translation: AAA59526.1.
AF021834 mRNA. Translation: AAD01700.1.
AY263365 Genomic DNA. Translation: AAO89075.1.
AC007319 Genomic DNA. Translation: AAY14807.1.
CH471058 Genomic DNA. Translation: EAX10921.1.
CH471058 Genomic DNA. Translation: EAX10922.1.
BC015514 mRNA. Translation: AAH15514.1.

IPI

IPI00021834.
IPI00218184.

PIR

TIHUGK. A23712.

RefSeq

NP_001027452.1. NM_001032281.2.
NP_006278.1. NM_006287.4.

UniGene

Hs.516578.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1ADZ	NMR	-	A	121-182	[»]
1IRH	NMR	-	A	210-270	[»]
1TFX	X-ray	2.60	C/D	121-178	[»]

ProteinModelPortal

P10646.

SMR

P10646. Positions 51-270.

ModBase

Search...

Protein-protein interaction databases

STRING

P10646.

Protein family/group databases

MEROPS

I02.011.

PTM databases

GlycoSuiteDB

P10646.

PhosphoSite

P10646.

Polymorphism databases

DMDM

125932.

Proteomic databases

PeptideAtlas

P10646.

PRIDE

P10646.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000233156; ENSP00000233156; ENSG00000003436.
ENST00000392365; ENSP00000376172; ENSG00000003436.

GeneID

7035.

KEGG

hsa:7035.

UCSC

uc002upx.1. human.
uc002uqa.1. human.

Organism-specific databases

CTD

7035.

GeneCards

GC02M188295.

H-InvDB

HIX0002660.

HGNC

HGNC:11760. TFPI.

HPA

CAB020842.
HPA005575.

MIM

152310. gene.

neXtProt

NX_P10646.

PharmGKB

PA36475.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG07340.

GeneTree

ENSGT00600000084247.

HOGENOM

HBG715101.

HOVERGEN

HBG056804.

InParanoid

P10646.

OMA

FIQRISK.

OrthoDB

EOG4MW86M.

PhylomeDB

P10646.

Enzyme and pathway databases

Pathway_Interaction_DB

syndecan_4_pathway. Syndecan-4-mediated signaling events.

Reactome

REACT_604. Hemostasis.

Gene expression databases

ArrayExpress

P10646.

Bgee

P10646.

CleanEx

HS_TFPI.

Genevestigator

P10646.

GermOnline

ENSG00000003436. Homo sapiens.

Family and domain databases

InterPro

IPR002223. Prot_inh_Kunz-m.
IPR008296. Prot_inhib_I2_TFPI.
IPR020901. Prtase_inh_Kunz-CS.
[Graphical view]

Gene3D

G3DSA:4.10.410.10. Prot_inh_Kunz-m. 3 hits.

KO

K03909.

Pfam

PF00014. Kunitz_BPTI. 3 hits.
[Graphical view]

PIRSF

PIRSF001620. TFPI. 1 hit.

PRINTS

PR00759. BASICPTASE.

SMART

SM00131. KU. 3 hits.
[Graphical view]

SUPFAM

SSF57362. Prot_inh_Kunz-m. 3 hits.

PROSITE

PS00280. BPTI_KUNITZ_1. 3 hits.
PS50279. BPTI_KUNITZ_2. 3 hits.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00036. Coagulation factor VIIa.

NextBio

27483.

PMAP-CutDB

P10646.

SOURCE

Search...

Entry information

Entry name

TFPI1_HUMAN

Accession

Primary (citable) accession number: P10646
Secondary accession number(s): O95103, Q53TS4

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1989
Last sequence update:	July 1, 1989
Last modified:	January 25, 2012
This is version 157 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.