P00750 (TPA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tissue-type plasminogen activator
Short name=t-PA
Short name=t-plasminogen activator
Short name=tPA
EC=3.4.21.68

Alternative name(s):
INN=Alteplase
INN=Reteplase

Cleaved into the following 2 chains:

1. Tissue-type plasminogen activator chain A
2. Tissue-type plasminogen activator chain B

Gene names

Name:

PLAT

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	562 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	Converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By controlling plasmin-mediated proteolysis, it plays an important role in tissue remodeling and degradation, in cell migration and many other physiopathological events. Plays a direct role in facilitating neuronal migration.
Catalytic activity	Specific cleavage of Arg-|-Val bond in plasminogen to form plasmin.
Enzyme regulation	Inhibited by SERPINA5. Ref.24
Subunit structure	Heterodimer of chain A and chain B held by a disulfide bond. Forms a heterodimer with SERPINA5. Binds to fibrin with high affinity. This interaction leads to an increase in the catalytic efficiency of the enzyme between 100-fold and 1000-fold, due to an increase in affinity for plasminogen. Similarly, binding to heparin increases the activation of plasminogen. Binds to annexin A2, cytokeratin-8, fibronectin and laminin. Binds to mannose receptor and the low-density lipoprotein receptor-related protein (LRP1); these proteins are involved in TPA clearance. Yet unidentified interactions on endothelial cells and vascular smooth muscle cells (VSMC) lead to a 100-fold stimulation of plasminogen activation. In addition, binding to VSMC reduces TPA inhibition by PAI-1 by 30-fold. Binds LRP1B; binding is followed by internalization and degradation. Ref.25
Subcellular location	Secreted › extracellular space.
Tissue specificity	Synthesized in numerous tissues (including tumors) and secreted into most extracellular body fluids, such as plasma, uterine fluid, saliva, gingival crevicular fluid, tears, seminal fluid, and milk.
Domain	Both FN1 and one of the kringle domains are required for binding to fibrin. Ref.33 Ref.34 Both FN1 and EGF-like domains are important for binding to LRP1. Ref.33 Ref.34 The FN1 domain mediates binding to annexin A2. Ref.33 Ref.34 The second kringle domain is implicated in binding to cytokeratin-8 and to the endothelial cell surface binding site. Ref.33 Ref.34
Post-translational modification	The single chain, almost fully active enzyme, can be further processed into a two-chain fully active form by a cleavage after Arg-310 catalyzed by plasmin, tissue kallikrein or factor Xa. Differential cell-specific N-linked glycosylation gives rise to two glycoforms, type I (glycosylated at Asn-219) and type II (not glycosylated at Asn-219). The single chain type I glycoform is less readily converted into the two-chain form by plasmin, and the two-chain type I glycoform has a lower activity than the two-chain type II glycoform in the presence of fibrin. Ref.21 Ref.22 N-glycosylation of Asn-152; the bound oligomannosidic glycan is involved in the interaction with the mannose receptor. Characterization of O-linked glycan was studied in Bowes melanoma cell line.
Involvement in disease	Increased activity of TPA results in increased fibrinolysis of fibrin blood clots that is associated with excessive bleeding. Defective release of TPA results in hypofibrinolysis that can lead to thrombosis or embolism.
Pharmaceutical use	Available under the names Activase (Genentech) and Retavase (Centocor and Roche) [Retavase is a fragment of TPA that contains kringle 2 and the protease domain; it was also known as BM 06.022]. Used in Acute Myocardial Infarction (AMI), in Acute Ischemic Stroke (AIS) and Pulmonary Embolism (PE) to initiate fibrinolysis.
Sequence similarities	Belongs to the peptidase S1 family. Contains 1 EGF-like domain. Contains 1 fibronectin type-I domain. Contains 2 kringle domains. Contains 1 peptidase S1 domain.

Ontologies

Keywords
Biological process	Plasminogen activation
Cellular component	Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Domain	EGF-like domain Kringle Repeat Signal
Molecular function	Hydrolase Protease Serine protease
PTM	Cleavage on pair of basic residues Disulfide bond Glycoprotein Zymogen
Technical term	3D-structure Complete proteome Direct protein sequencing Pharmaceutical Reference proteome
Gene Ontology (GO)
Biological_process	blood coagulation Traceable author statement. Source: Reactome cellular protein modification process Traceable author statement PubMed 3087818. Source: ProtInc fibrinolysis Traceable author statement. Source: Reactome negative regulation of proteolysis Inferred from direct assay PubMed 1695900. Source: BHF-UCL plasminogen activation Inferred from direct assay PubMed 12694198. Source: UniProtKB platelet-derived growth factor receptor signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of ovulation Inferred from electronic annotation. Source: Compara proteolysis Traceable author statement PubMed 3087818. Source: ProtInc regulation of synaptic plasticity Inferred from electronic annotation. Source: Compara response to cAMP Inferred from electronic annotation. Source: Compara response to glucocorticoid stimulus Inferred from electronic annotation. Source: Compara response to hypoxia Inferred from electronic annotation. Source: Compara response to peptide hormone stimulus Inferred from electronic annotation. Source: Compara smooth muscle cell migration Inferred from electronic annotation. Source: Compara synaptic transmission, glutamatergic Inferred from electronic annotation. Source: Compara
Cellular_component	apical part of cell Inferred from electronic annotation. Source: Compara cell surface Inferred from direct assay PubMed 1632457. Source: BHF-UCL cytoplasm Inferred from direct assay PubMed 1632457. Source: BHF-UCL extracellular region Traceable author statement. Source: Reactome extracellular space Inferred from electronic annotation. Source: UniProtKB-SubCell secretory granule Inferred from electronic annotation. Source: Compara synapse Inferred from electronic annotation. Source: Compara
Molecular_function	serine-type endopeptidase activity Inferred from direct assay PubMed 1695900PubMed 8508955. Source: BHF-UCL
Complete GO annotation...

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P00750-1)

Also known as: Long;

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 2 (identifier: P00750-2)

Also known as: Short;

The sequence of this isoform differs from the canonical sequence as follows:
     269-291: NPDGDAKPWCHVLKNRRLTWEYC → TGRSVSSPATASMRPCPLSIRSG
     292-562: Missing.

Note: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoform 3 (identifier: P00750-3)

The sequence of this isoform differs from the canonical sequence as follows:
     39-85: VICRDEKTQMIYQQHQSWLRPVLRSNRVEYCWCNSGRAQCHSVPVKS → G

Note: No experimental confirmation available.

Isoform 4 (identifier: P00750-4)

Also known as: Neonatal;

The sequence of this isoform differs from the canonical sequence as follows:
     1-40: MDAMKRGLCCVLLLCGAVFVSPSQEIHARFRRGARSYQVI → MAS
     79-208: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 22

22

Propeptide

23 – 32

10

PRO_0000028348

Propeptide

33 – 35

3

Removed by plasmin

PRO_0000028349

Chain

36 – 562

527

Tissue-type plasminogen activator

PRO_0000028350

Chain

36 – 310

275

Tissue-type plasminogen activator chain A

PRO_0000028351

Chain

311 – 562

252

Tissue-type plasminogen activator chain B

PRO_0000028352

Regions

Domain

39 – 81

43

Fibronectin type-I

Domain

82 – 120

39

EGF-like

Domain

127 – 208

82

Kringle 1

Domain

215 – 296

82

Kringle 2

Domain

311 – 561

251

Peptidase S1

Region

42 – 52

11

Important for binding to annexin A2

Sites

Active site

357

1

Charge relay system

Active site

406

1

Charge relay system

Active site

513

1

Charge relay system

Site

102

1

Important for binding to LRP1

Site

253

1

Not glycosylated

Site

464

1

Important for single-chain activity

Site

512

1

Important for single-chain activity

Amino acid modifications

Glycosylation

96

1

O-linked (Fuc) Ref.22

CAR_000029

Glycosylation

152

1

N-linked (GlcNAc...)

Glycosylation

219

1

N-linked (GlcNAc...); partial

CAR_000030

Glycosylation

483

1

N-linked (GlcNAc...)

CAR_000031

Disulfide bond

41 ↔ 71

Ref.23

Disulfide bond

69 ↔ 78

Ref.23

Disulfide bond

86 ↔ 97

Ref.23

Disulfide bond

91 ↔ 108

Ref.23

Disulfide bond

110 ↔ 119

Ref.23

Disulfide bond

127 ↔ 208

By similarity

Disulfide bond

148 ↔ 190

By similarity

Disulfide bond

179 ↔ 203

By similarity

Disulfide bond

215 ↔ 296

Ref.23

Disulfide bond

236 ↔ 278

Ref.23

Disulfide bond

267 ↔ 291

Ref.23

Disulfide bond

299 ↔ 430

Interchain (between A and B chains) Ref.23

Disulfide bond

342 ↔ 358

By similarity

Disulfide bond

350 ↔ 419

By similarity

Disulfide bond

444 ↔ 519

By similarity

Disulfide bond

476 ↔ 492

By similarity

Disulfide bond

509 ↔ 537

By similarity

Natural variations

Alternative sequence

1 – 40

40

MDAMK…SYQVI → MAS in isoform 4.

VSP_028029

Alternative sequence

39 – 85

47

VICRD…VPVKS → G in isoform 3.

VSP_015957

Alternative sequence

79 – 208

130

Missing in isoform 4.

VSP_028030

Alternative sequence

269 – 291

23

NPDGD…TWEYC → TGRSVSSPATASMRPCPLSI RSG in isoform 2.

VSP_005411

Alternative sequence

292 – 562

271

Missing in isoform 2.

VSP_005412

Natural variant

34

1

A → D. Ref.12
Corresponds to variant rs8178733 [ dbSNP | Ensembl ].

VAR_020181

Natural variant

136

1

R → S. Ref.12
Corresponds to variant rs8178747 [ dbSNP | Ensembl ].

VAR_038732

Natural variant

146

1

A → T. Ref.12
Corresponds to variant rs8178748 [ dbSNP | Ensembl ].

VAR_038733

Natural variant

164

1

R → W. Ref.12
Corresponds to variant rs2020921 [ dbSNP | Ensembl ].

VAR_011783

Experimental info

Sequence conflict

93

1

N → T in AAB59510. Ref.2

Sequence conflict

159 – 160

2

KP → NA in CAA31489. Ref.7

Sequence conflict

247

1

K → N in AAO34406. Ref.9

Sequence conflict

283

1

N → S in AAH95403. Ref.14

Sequence conflict

333 – 334

2

RR → EE in AAK11956. Ref.8

Sequence conflict

389

1

V → C in AAK11956. Ref.8

Secondary structure

1

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562

Helix Strand Turn

Details...

Beta strand

41 – 43

3

Beta strand

44 – 46

3

Beta strand

48 – 50

3

Beta strand

55 – 59

5

Beta strand

61 – 64

4

Beta strand

66 – 70

5

Beta strand

72 – 74

3

Beta strand

77 – 81

5

Beta strand

83 – 85

3

Beta strand

96 – 104

9

Beta strand

106 – 109

4

Beta strand

115 – 118

4

Beta strand

221 – 223

3

Beta strand

229 – 233

5

Helix

242 – 244

3

Beta strand

248 – 250

3

Beta strand

251 – 253

3

Helix

256 – 259

4

Beta strand

262 – 264

3

Beta strand

277 – 282

6

Beta strand

285 – 291

7

Beta strand

309 – 311

3

Beta strand

312 – 316

5

Helix

319 – 321

3

Beta strand

325 – 331

7

Beta strand

338 – 346

9

Beta strand

348 – 354

7

Helix

356 – 359

4

Helix

365 – 367

3

Beta strand

368 – 373

6

Beta strand

375 – 379

5

Beta strand

385 – 394

10

Turn

400 – 402

3

Beta strand

408 – 412

5

Beta strand

415 – 417

3

Beta strand

424 – 426

3

Beta strand

443 – 449

7

Beta strand

451 – 453

3

Beta strand

464 – 470

7

Helix

473 – 475

3

Turn

478 – 483

6

Beta strand

490 – 494

5

Beta strand

500 – 502

3

Beta strand

516 – 521

6

Beta strand

524 – 533

10

Beta strand

535 – 538

4

Beta strand

544 – 548

5

Helix

549 – 552

4

Helix

553 – 559

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Long) [UniParc]. Last modified July 21, 1986. Version 1. Checksum: B7EC9B1A5E3FDC4D	FASTA	562	62,917
	10 20 30 40 50 60 MDAMKRGLCC VLLLCGAVFV SPSQEIHARF RRGARSYQVI CRDEKTQMIY QQHQSWLRPV 70 80 90 100 110 120 LRSNRVEYCW CNSGRAQCHS VPVKSCSEPR CFNGGTCQQA LYFSDFVCQC PEGFAGKCCE 130 140 150 160 170 180 IDTRATCYED QGISYRGTWS TAESGAECTN WNSSALAQKP YSGRRPDAIR LGLGNHNYCR 190 200 210 220 230 240 NPDRDSKPWC YVFKAGKYSS EFCSTPACSE GNSDCYFGNG SAYRGTHSLT ESGASCLPWN 250 260 270 280 290 300 SMILIGKVYT AQNPSAQALG LGKHNYCRNP DGDAKPWCHV LKNRRLTWEY CDVPSCSTCG 310 320 330 340 350 360 LRQYSQPQFR IKGGLFADIA SHPWQAAIFA KHRRSPGERF LCGGILISSC WILSAAHCFQ 370 380 390 400 410 420 ERFPPHHLTV ILGRTYRVVP GEEEQKFEVE KYIVHKEFDD DTYDNDIALL QLKSDSSRCA 430 440 450 460 470 480 QESSVVRTVC LPPADLQLPD WTECELSGYG KHEALSPFYS ERLKEAHVRL YPSSRCTSQH 490 500 510 520 530 540 LLNRTVTDNM LCAGDTRSGG PQANLHDACQ GDSGGPLVCL NDGRMTLVGI ISWGLGCGQK 550 560 DVPGVYTKVT NYLDWIRDNM RP
	Isoform 2 (Short) [UniParc]. Checksum: 874E38C52F50FF5D	FASTA	291	32,175
	10 20 30 40 50 60 MDAMKRGLCC VLLLCGAVFV SPSQEIHARF RRGARSYQVI CRDEKTQMIY QQHQSWLRPV 70 80 90 100 110 120 LRSNRVEYCW CNSGRAQCHS VPVKSCSEPR CFNGGTCQQA LYFSDFVCQC PEGFAGKCCE 130 140 150 160 170 180 IDTRATCYED QGISYRGTWS TAESGAECTN WNSSALAQKP YSGRRPDAIR LGLGNHNYCR 190 200 210 220 230 240 NPDRDSKPWC YVFKAGKYSS EFCSTPACSE GNSDCYFGNG SAYRGTHSLT ESGASCLPWN 250 260 270 280 290 SMILIGKVYT AQNPSAQALG LGKHNYCRTG RSVSSPATAS MRPCPLSIRS G
	Isoform 3 [UniParc]. Checksum: BAB31901FDC96800	FASTA	516	57,371
	10 20 30 40 50 60 MDAMKRGLCC VLLLCGAVFV SPSQEIHARF RRGARSYQGC SEPRCFNGGT CQQALYFSDF 70 80 90 100 110 120 VCQCPEGFAG KCCEIDTRAT CYEDQGISYR GTWSTAESGA ECTNWNSSAL AQKPYSGRRP 130 140 150 160 170 180 DAIRLGLGNH NYCRNPDRDS KPWCYVFKAG KYSSEFCSTP ACSEGNSDCY FGNGSAYRGT 190 200 210 220 230 240 HSLTESGASC LPWNSMILIG KVYTAQNPSA QALGLGKHNY CRNPDGDAKP WCHVLKNRRL 250 260 270 280 290 300 TWEYCDVPSC STCGLRQYSQ PQFRIKGGLF ADIASHPWQA AIFAKHRRSP GERFLCGGIL 310 320 330 340 350 360 ISSCWILSAA HCFQERFPPH HLTVILGRTY RVVPGEEEQK FEVEKYIVHK EFDDDTYDND 370 380 390 400 410 420 IALLQLKSDS SRCAQESSVV RTVCLPPADL QLPDWTECEL SGYGKHEALS PFYSERLKEA 430 440 450 460 470 480 HVRLYPSSRC TSQHLLNRTV TDNMLCAGDT RSGGPQANLH DACQGDSGGP LVCLNDGRMT 490 500 510 LVGIISWGLG CGQKDVPGVY TKVTNYLDWI RDNMRP
	Isoform 4 (Neonatal) [UniParc]. Checksum: 55BB9FB94F65DF4F	FASTA	395	44,373
	10 20 30 40 50 60 MASCRDEKTQ MIYQQHQSWL RPVLRSNRVE YCWCNSGRAQ CSEGNSDCYF GNGSAYRGTH 70 80 90 100 110 120 SLTESGASCL PWNSMILIGK VYTAQNPSAQ ALGLGKHNYC RNPDGDAKPW CHVLKNRRLT 130 140 150 160 170 180 WEYCDVPSCS TCGLRQYSQP QFRIKGGLFA DIASHPWQAA IFAKHRRSPG ERFLCGGILI 190 200 210 220 230 240 SSCWILSAAH CFQERFPPHH LTVILGRTYR VVPGEEEQKF EVEKYIVHKE FDDDTYDNDI 250 260 270 280 290 300 ALLQLKSDSS RCAQESSVVR TVCLPPADLQ LPDWTECELS GYGKHEALSP FYSERLKEAH 310 320 330 340 350 360 VRLYPSSRCT SQHLLNRTVT DNMLCAGDTR SGGPQANLHD ACQGDSGGPL VCLNDGRMTL 370 380 390 VGIISWGLGC GQKDVPGVYT KVTNYLDWIR DNMRP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli." Pennica D., Holmes W.E., Kohr W.J., Harkins R.N., Vehar G.A., Ward C.A., Bennett W.F., Yelverton E., Seeburg P.H., Heyneker H.L., Goeddel D.V., Collen D. Nature 301:214-221(1983) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Melanoma.
[2]	"The structure of the human tissue-type plasminogen activator gene: correlation of intron and exon structures to functional and structural domains." Ny T., Elgh F., Lund B. Proc. Natl. Acad. Sci. U.S.A. 81:5355-5359(1984) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"The human tissue plasminogen activator gene." Friezner Degen S.J., Rajput B., Reich E. J. Biol. Chem. 261:6972-6985(1986) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Cloning of cDNA coding for human tissue-type plasminogen activator and its expression in Escherichia coli." Harris T.J., Patel T., Marston F.A., Little S., Emtage J.S., Opdenakker G., Volckaert G., Rombauts W., Billiau A., Somer P. Mol. Biol. Med. 3:279-292(1986) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[5]	"Expression of human uterine tissue-type plasminogen activator in mouse cells using BPV vectors." Reddy V.B., Garramone A.J., Sasak H., Wei C.-M., Watkins P., Galli J., Hsiung N. DNA 6:461-472(1987) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[6]	"Nucleotide sequence of the tissue-type plasminogen activator cDNA from human fetal lung cells." Sasaki H., Saito Y., Hayashi M., Otsuka K., Niwa M. Nucleic Acids Res. 16:5695-5695(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Fetal lung.
[7]	"Variant tissue-type plasminogen activator (PLAT) cDNA obtained from human endothelial cells." Siebert P.D., Fong K. Nucleic Acids Res. 18:1086-1086(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Umbilical vein.
[8]	"A brain-type plasminogen activator." Dou D. Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
[9]	"cDNA of tissue plasminogen activator." Liu Y., Xu L., Zeng Y., He X. Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[10]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). Tissue: Testis.
[11]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[12]	SeattleSNPs variation discovery resource Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ASP-34; SER-136; THR-146 AND TRP-164.
[13]	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 (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[14]	"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] (ISOFORMS 1 AND 3). Tissue: Brain, Placenta and Skin.
[15]	"Isolation and characterization of the human tissue-type plasminogen activator structural gene including its 5' flanking region." Fisher R., Waller E.K., Grossi G., Thompson D., Tizard R., Schleuning W.-D. J. Biol. Chem. 260:11223-11230(1985) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-36.
[16]	"Purification and characterization of tissue plasminogen activator secreted by human embryonic lung diploid fibroblasts, IMR-90 cells." Itagaki Y., Yasuda H., Morinaga T., Mitsuda S., Higashio K. Agric. Biol. Chem. 55:1225-1232(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 31-562.
[17]	"Purification and characterization of a melanoma cell plasminogen activator." Wallen P., Pohl G., Bergsdorf N., Raanby M., Ny T., Joernvall H. Eur. J. Biochem. 132:681-686(1983) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 33-52 AND 311-330. Tissue: Melanoma.
[18]	"Tissue plasminogen activator: peptide analyses confirm an indirectly derived amino acid sequence, identify the active site serine residue, establish glycosylation sites, and localize variant differences." Pohl G., Kaellstroem M., Bergsdorf N., Wallen P., Joernvall H. Biochemistry 23:3701-3707(1984) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 36-562. Tissue: Melanoma.
[19]	"Isolation of cDNA sequences coding for a part of human tissue plasminogen activator." Edlund T., Ny T., Raanby M., Heden L.-O., Palm G., Holmgren E., Josephson S. Proc. Natl. Acad. Sci. U.S.A. 80:349-352(1983) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 251-358.
[20]	Jalah R., Pavlakis G.N., Felber B.J. Submitted (JUL-2007) to UniProtKB Cited for: PARTIAL PROTEIN SEQUENCE, SIGNAL SEQUENCE CLEAVAGE SITE.
[21]	"Carbohydrate structure of recombinant human uterine tissue plasminogen activator expressed in mouse epithelial cells." Pfeiffer G., Schmidt M., Strube K.-H., Geyer R. Eur. J. Biochem. 186:273-286(1989) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE OF CARBOHYDRATES.
[22]	"Tissue plasminogen activator has an O-linked fucose attached to threonine-61 in the epidermal growth factor domain." Harris R.J., Leonard C.K., Guzzetta A.W., Spellman M.W. Biochemistry 30:2311-2314(1991) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION AT THR-96.
[23]	"Disulfide pairing of the recombinant kringle-2 domain of tissue plasminogen activator produced in Escherichia coli." Vlahos C.J., Wilhelm O.G., Hassell T., Jaskunas S.R., Bang N.U. J. Biol. Chem. 266:10070-10072(1991) [PubMed] [Europe PMC] [Abstract] Cited for: DISULFIDE BONDS IN KRINGLE 2.
[24]	"Functionally inactive protein C inhibitor in seminal plasma may be associated with infertility." He S., Lin Y.L., Liu Y.X. Mol. Hum. Reprod. 5:513-519(1999) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION, HETERODIMER WITH SERPINA5.
[25]	"The putative tumor suppressor LRP1B, a novel member of the low density lipoprotein (LDL) receptor family, exhibits both overlapping and distinct properties with the LDL receptor-related protein." Liu C.-X., Li Y., Obermoeller-McCormick L.M., Schwartz A.L., Bu G. J. Biol. Chem. 276:28889-28896(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH LRP1B.
[26]	"An unappreciated role for RNA surveillance." Hillman R.T., Green R.E., Brenner S.E. Genome Biol. 5:R8.1-R8.16(2004) [PubMed] [Europe PMC] [Abstract] Cited for: SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
[27]	"1H NMR structural characterization of a recombinant kringle 2 domain from human tissue-type plasminogen activator." Byeon I.-J.L., Kelley R.F., Llinas M. Biochemistry 28:9350-9360(1989) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF KRINGLE 2.
[28]	"Kringle-2 domain of the tissue-type plasminogen activator. 1H-NMR assignments and secondary structure." Byeon I.-J.L., Kelley R.F., Llinas M. Eur. J. Biochem. 197:155-165(1991) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF KRINGLE 2.
[29]	"Solution structure of the tissue-type plasminogen activator kringle 2 domain complexed to 6-aminohexanoic acid an antifibrinolytic drug." Byeon I.-J.L., Llinas M. J. Mol. Biol. 222:1035-1051(1991) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF KRINGLE 2.
[30]	"Crystal structure of the kringle 2 domain of tissue plasminogen activator at 2.4-A resolution." de Vos A., Ultsch M.H., Kelley R.F., Padmanabhan K., Tulinskly A., Westbrook M.L., Kossiakof A.A. Biochemistry 31:270-279(1992) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF KRINGLE 2.
[31]	"Solution structure of the fibrin binding finger domain of tissue-type plasminogen activator determined by 1H nuclear magnetic resonance." Downing A.K., Driscoll P.C., Harvey T.S., Dudgeon T.J., Smith B.O., Baron M., Campbell I.D. J. Mol. Biol. 225:821-833(1992) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 38-85.
[32]	"The solution structure and backbone dynamics of the fibronectin type I and epidermal growth factor-like pair of modules of tissue-type plasminogen activator." Smith B.O., Downing A.K., Driscoll P.C., Dudgeon T.J., Campbell I.D. Structure 3:823-833(1995) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 36-126.
[33]	"The 2.3 A crystal structure of the catalytic domain of recombinant two-chain human tissue-type plasminogen activator." Lamba D., Bauer M., Huber R., Fischer S., Rudolph R., Kohnert U., Bode W. J. Mol. Biol. 258:117-135(1996) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF CATALYTIC DOMAIN.
[34]	"Lysine 156 promotes the anomalous proenzyme activity of tPA: X-ray crystal structure of single-chain human tPA." Renatus M., Engh R.A., Stubbs M.T., Huber R., Fischer S., Kohnert U., Bode W. EMBO J. 16:4797-4805(1997) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF CATALYTIC DOMAIN.
+	Additional computationally mapped references.

Web resources

Wikipedia

Tissue plasminogen activator entry

SeattleSNPs

SHMPD

The Singapore human mutation and polymorphism database

Activase

Clinical information on Activase

Retavase

Clinical information on Retavase

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L00153 , L00141, L00142, L00143, L00144, L00145, L00146, L00147, L00148, L00149, L00150, L00151 Genomic DNA. Translation: AAB59510.1.
K03021 Genomic DNA. Translation: AAA98809.1.
M15518 mRNA. Translation: AAA60111.1.
M18182 mRNA. Translation: AAA36800.1.
X07393 mRNA. Translation: CAA30302.1.
X13097 mRNA. Translation: CAA31489.1.
AF260825 mRNA. Translation: AAK11956.1.
AY221101 mRNA. Translation: AAO34406.1.
AK289387 mRNA. Translation: BAF82076.1.
AK290575 mRNA. Translation: BAF83264.1.
AK313342 mRNA. Translation: BAG36145.1.
BT007060 mRNA. Translation: AAP35709.1.
AY291060 Genomic DNA. Translation: AAP34246.1.
CH471080 Genomic DNA. Translation: EAW63235.1.
CH471080 Genomic DNA. Translation: EAW63233.1.
BC002795 mRNA. Translation: AAH02795.3.
BC007231 mRNA. Translation: AAH07231.1.
BC013968 mRNA. Translation: AAH13968.3.
BC018636 mRNA. Translation: AAH18636.3.
BC095403 mRNA. Translation: AAH95403.1.
M11890, M11889 Genomic DNA. Translation: AAA61213.1.
D01096 mRNA. Translation: BAA00881.1.
V00570 mRNA. Translation: CAA23833.1.

IPI

IPI00019590.
IPI00295285.
IPI00479511.
IPI00910450.

PIR

UKHUT. A94004.
I38098.

RefSeq

NP_000921.1. NM_000930.3.
NP_127509.1. NM_033011.2.

UniGene

Hs.491582.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1A5H	X-ray	2.90	A/B	311-562	[»]
			C/D	298-304	[»]
1BDA	X-ray	3.35	A/B	298-562	[»]
1PK2	NMR	-	A	209-298	[»]
1PML	X-ray	2.38	A/B/C	213-298	[»]
1RTF	X-ray	2.30	B	311-562	[»]
1TPG	NMR	-	A	36-126	[»]
1TPK	X-ray	2.40	A/B/C	211-298	[»]
1TPM	NMR	-	A	36-85	[»]
1TPN	NMR	-	A	36-85	[»]

ProteinModelPortal

P00750.

ModBase

Search...

Protein-protein interaction databases

IntAct

P00750. 1 interaction.

MINT

MINT-8309345.

Protein family/group databases

MEROPS

S01.232.

PTM databases

GlycoSuiteDB

P00750.

PhosphoSite

P00750.

Polymorphism databases

DMDM

137119.

Proteomic databases

PaxDb

P00750.

PRIDE

P00750.

Protocols and materials databases

DNASU

5327.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000220809; ENSP00000220809; ENSG00000104368.
ENST00000352041; ENSP00000270188; ENSG00000104368.
ENST00000429089; ENSP00000392045; ENSG00000104368.

GeneID

5327.

KEGG

hsa:5327.

UCSC

uc003xos.2. human.
uc003xot.2. human.

Organism-specific databases

CTD

5327.

GeneCards

GC08M042032.

HGNC

HGNC:9051. PLAT.

HPA

CAB009335.
HPA003412.

MIM

173370. gene.

neXtProt

NX_P00750.

PharmGKB

PA33381.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5640.

HOVERGEN

HBG008633.

InParanoid

P00750.

KO

K01343.

OMA

AHVRLYP.

OrthoDB

EOG4BVRTC.

PhylomeDB

P00750.

Enzyme and pathway databases

BRENDA

3.4.21.68. 2681.

Pathway_Interaction_DB

amb2_neutrophils_pathway. amb2 Integrin signaling.

Reactome

REACT_111102. Signal Transduction.
REACT_604. Hemostasis.

Gene expression databases

ArrayExpress

P00750.

Bgee

P00750.

Genevestigator

P00750.

GermOnline

ENSG00000104368. Homo sapiens.

Family and domain databases

Gene3D

2.40.20.10. 2 hits.

InterPro

IPR000742. EG-like_dom.
IPR013032. EGF-like_CS.
IPR000083. Fibronectin_type1.
IPR000001. Kringle.
IPR013806. Kringle-like.
IPR018056. Kringle_CS.
IPR001254. Peptidase_S1.
IPR018114. Peptidase_S1_AS.
IPR001314. Peptidase_S1A.
IPR026280. Tissue_plasm_act.
IPR009003. Trypsin-like_Pept_dom.
[Graphical view]

Pfam

PF00008. EGF. 1 hit.
PF00039. fn1. 1 hit.
PF00051. Kringle. 2 hits.
PF00089. Trypsin. 1 hit.
[Graphical view]

PIRSF

PIRSF001145. Tissue_plasm_act. 1 hit.

PRINTS

PR00722. CHYMOTRYPSIN.

SMART

SM00181. EGF. 1 hit.
SM00058. FN1. 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.

PROSITE

PS00022. EGF_1. 1 hit.
PS01186. EGF_2. 1 hit.
PS50026. EGF_3. 1 hit.
PS01253. FN1_1. 1 hit.
PS51091. FN1_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

BindingDB

P00750.

ChEMBL

CHEMBL1873.

ChiTaRS

PLAT. human.

DrugBank

DB00009. Alteplase.
DB00513. Aminocaproic Acid.
DB00029. Anistreplase.
DB01088. Iloprost.
DB00015. Reteplase.
DB00031. Tenecteplase.
DB00302. Tranexamic Acid.
DB00013. Urokinase.

EvolutionaryTrace

P00750.

GenomeRNAi

5327.

NextBio

20622.

PMAP-CutDB

B2R8E8.

SOURCE

Search...

Entry information

Entry name

TPA_HUMAN

Accession

Primary (citable) accession number: P00750
Secondary accession number(s): A8K022 , B2R8E8, Q15103, Q503B0, Q6PJA5, Q7Z7N2, Q86YK8, Q9BU99, Q9BZW1

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	July 21, 1986
Last modified:	May 29, 2013
This is version 187 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.