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Protein

Tissue-type plasminogen activator

Gene

PLAT

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 activityi

Specific cleavage of Arg-|-Val bond in plasminogen to form plasmin.

Enzyme regulationi

Inhibited by SERPINA5.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei102Important for binding to LRP11
Active sitei357Charge relay system1
Active sitei406Charge relay system1
Sitei464Important for single-chain activity1
Sitei512Important for single-chain activity1
Active sitei513Charge relay system1

GO - Molecular functioni

  • phosphoprotein binding Source: AgBase
  • receptor binding Source: AgBase
  • serine-type endopeptidase activity Source: BHF-UCL

GO - Biological processi

  • blood coagulation Source: ProtInc
  • cellular protein modification process Source: ProtInc
  • fibrinolysis Source: Reactome
  • negative regulation of proteolysis Source: BHF-UCL
  • plasminogen activation Source: UniProtKB
  • platelet-derived growth factor receptor signaling pathway Source: Ensembl
  • proteolysis Source: ProtInc
  • response to hypoxia Source: Ensembl
  • smooth muscle cell migration Source: Ensembl

Keywordsi

Molecular functionHydrolase, Protease, Serine protease
Biological processPlasminogen activation

Enzyme and pathway databases

BRENDAi3.4.21.68 2681
ReactomeiR-HSA-186797 Signaling by PDGF
R-HSA-75205 Dissolution of Fibrin Clot
SIGNORiP00750

Protein family/group databases

MEROPSiS01.232

Names & Taxonomyi

Protein namesi
Recommended name:
Tissue-type plasminogen activator (EC:3.4.21.68)
Short name:
t-PA
Short name:
t-plasminogen activator
Short name:
tPA
Alternative name(s):
INN: Alteplase
INN: Reteplase
Cleaved into the following 2 chains:
Gene namesi
Name:PLAT
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 8

Organism-specific databases

EuPathDBiHostDB:ENSG00000104368.17
HGNCiHGNC:9051 PLAT
MIMi173370 gene
neXtProtiNX_P00750

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Involvement in diseasei

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.1 Publication

Pharmaceutical usei

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.

Organism-specific databases

DisGeNETi5327
MalaCardsiPLAT
OpenTargetsiENSG00000104368
PharmGKBiPA33381

Chemistry databases

ChEMBLiCHEMBL1873
DrugBankiDB07684 5-(DIMETHYLAMINO)-2-NAPHTHALENESULFONIC ACID
DB00513 Aminocaproic Acid
DB06404 C1 Esterase Inhibitor (Human)
DB09228 C1 Esterase Inhibitor (Recombinant)
DB01050 Ibuprofen
DB01088 Iloprost
DB00013 Urokinase
GuidetoPHARMACOLOGYi2392

Polymorphism and mutation databases

BioMutaiPLAT
DMDMi137119

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 221 PublicationAdd BLAST22
PropeptideiPRO_000002834823 – 321 Publication10
PropeptideiPRO_000002834933 – 35Removed by plasmin1 Publication3
ChainiPRO_000002835036 – 562Tissue-type plasminogen activatorAdd BLAST527
ChainiPRO_000002835136 – 310Tissue-type plasminogen activator chain AAdd BLAST275
ChainiPRO_0000028352311 – 562Tissue-type plasminogen activator chain BAdd BLAST252

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi41 ↔ 711 Publication
Disulfide bondi69 ↔ 781 Publication
Disulfide bondi86 ↔ 971 Publication
Disulfide bondi91 ↔ 1081 Publication
GlycosylationiCAR_00002996O-linked (Fuc) threonine1 Publication1
Disulfide bondi110 ↔ 1191 Publication
Disulfide bondi127 ↔ 208By similarity
Disulfide bondi148 ↔ 190By similarity
Glycosylationi152N-linked (GlcNAc...) asparagine1 Publication1
Disulfide bondi179 ↔ 203By similarity
Disulfide bondi215 ↔ 2961 Publication
GlycosylationiCAR_000030219N-linked (GlcNAc...) asparagine; partial1 Publication1
Disulfide bondi236 ↔ 2781 Publication
Disulfide bondi267 ↔ 2911 Publication
Disulfide bondi299 ↔ 430Interchain (between A and B chains)PROSITE-ProRule annotation1 Publication
Disulfide bondi342 ↔ 358By similarity
Disulfide bondi350 ↔ 419By similarity
Disulfide bondi444 ↔ 519By similarity
Disulfide bondi476 ↔ 492By similarity
GlycosylationiCAR_000031483N-linked (GlcNAc...) asparagine1 Publication1
Disulfide bondi509 ↔ 537By similarity

Post-translational modificationi

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.1 Publication
N-glycosylation of Asn-152; the bound oligomannosidic glycan is involved in the interaction with the mannose receptor.1 Publication
Characterization of O-linked glycan was studied in Bowes melanoma cell line.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei253Not glycosylated1

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein, Zymogen

Proteomic databases

MaxQBiP00750
PaxDbiP00750
PeptideAtlasiP00750
PRIDEiP00750

PTM databases

GlyConnecti503
603
iPTMnetiP00750
PhosphoSitePlusiP00750
UniCarbKBiP00750

Miscellaneous databases

PMAP-CutDBiB2R8E8

Expressioni

Tissue specificityi

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.

Gene expression databases

BgeeiENSG00000104368
ExpressionAtlasiP00750 baseline and differential
GenevisibleiP00750 HS

Organism-specific databases

HPAiCAB009335
HPA003412

Interactioni

Subunit structurei

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.

GO - Molecular functioni

  • phosphoprotein binding Source: AgBase
  • receptor binding Source: AgBase

Protein-protein interaction databases

BioGridi111343, 40 interactors
ELMiP00750
IntActiP00750, 2 interactors
MINTiP00750
STRINGi9606.ENSP00000220809

Chemistry databases

BindingDBiP00750

Structurei

Secondary structure

1562
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi41 – 43Combined sources3
Beta strandi44 – 46Combined sources3
Beta strandi48 – 50Combined sources3
Beta strandi55 – 59Combined sources5
Beta strandi61 – 64Combined sources4
Beta strandi66 – 70Combined sources5
Beta strandi72 – 74Combined sources3
Beta strandi77 – 81Combined sources5
Beta strandi83 – 85Combined sources3
Beta strandi96 – 104Combined sources9
Beta strandi106 – 109Combined sources4
Beta strandi115 – 118Combined sources4
Beta strandi221 – 223Combined sources3
Beta strandi229 – 233Combined sources5
Helixi242 – 244Combined sources3
Beta strandi248 – 250Combined sources3
Beta strandi251 – 253Combined sources3
Helixi256 – 259Combined sources4
Beta strandi262 – 264Combined sources3
Beta strandi277 – 282Combined sources6
Beta strandi285 – 291Combined sources7
Beta strandi309 – 311Combined sources3
Beta strandi312 – 316Combined sources5
Helixi319 – 321Combined sources3
Beta strandi325 – 331Combined sources7
Beta strandi338 – 346Combined sources9
Beta strandi348 – 354Combined sources7
Helixi356 – 359Combined sources4
Helixi365 – 367Combined sources3
Beta strandi368 – 373Combined sources6
Beta strandi375 – 379Combined sources5
Beta strandi385 – 394Combined sources10
Turni400 – 402Combined sources3
Beta strandi408 – 412Combined sources5
Beta strandi415 – 417Combined sources3
Beta strandi423 – 425Combined sources3
Beta strandi443 – 449Combined sources7
Beta strandi451 – 453Combined sources3
Beta strandi464 – 470Combined sources7
Helixi473 – 475Combined sources3
Turni478 – 483Combined sources6
Beta strandi490 – 494Combined sources5
Beta strandi499 – 501Combined sources3
Beta strandi516 – 521Combined sources6
Beta strandi524 – 533Combined sources10
Beta strandi535 – 538Combined sources4
Beta strandi544 – 548Combined sources5
Helixi549 – 552Combined sources4
Helixi553 – 559Combined sources7

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1A5HX-ray2.90A/B311-562[»]
C/D298-304[»]
1BDAX-ray3.35A/B298-562[»]
1PK2NMR-A209-298[»]
1PMLX-ray2.38A/B/C213-298[»]
1RTFX-ray2.30B311-562[»]
1TPGNMR-A36-126[»]
1TPKX-ray2.40A/B/C211-298[»]
1TPMNMR-A36-85[»]
1TPNNMR-A36-85[»]
5BRRX-ray3.16E311-562[»]
ProteinModelPortaliP00750
SMRiP00750
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP00750

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini39 – 81Fibronectin type-IPROSITE-ProRule annotationAdd BLAST43
Domaini82 – 120EGF-likePROSITE-ProRule annotationAdd BLAST39
Domaini127 – 208Kringle 1PROSITE-ProRule annotationAdd BLAST82
Domaini215 – 296Kringle 2PROSITE-ProRule annotationAdd BLAST82
Domaini311 – 561Peptidase S1PROSITE-ProRule annotationAdd BLAST251

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni42 – 52Important for binding to annexin A2Add BLAST11

Domaini

Both FN1 and one of the kringle domains are required for binding to fibrin.
Both FN1 and EGF-like domains are important for binding to LRP1.
The FN1 domain mediates binding to annexin A2.
The second kringle domain is implicated in binding to cytokeratin-8 and to the endothelial cell surface binding site.

Sequence similaritiesi

Belongs to the peptidase S1 family.PROSITE-ProRule annotation

Keywords - Domaini

EGF-like domain, Kringle, Repeat, Signal

Phylogenomic databases

eggNOGiKOG3627 Eukaryota
COG5640 LUCA
GeneTreeiENSGT00760000119133
HOVERGENiHBG008633
InParanoidiP00750
KOiK01343
OMAiAHVRLYP
OrthoDBiEOG091G0AH5
PhylomeDBiP00750
TreeFamiTF329901

Family and domain databases

CDDicd00190 Tryp_SPc, 1 hit
Gene3Di2.40.20.10, 2 hits
InterProiView protein in InterPro
IPR013032 EGF-like_CS
IPR000742 EGF-like_dom
IPR000083 Fibronectin_type1
IPR000001 Kringle
IPR013806 Kringle-like
IPR018056 Kringle_CS
IPR038178 Kringle_sf
IPR009003 Peptidase_S1_PA
IPR001314 Peptidase_S1A
IPR026280 Tissue_plasm_act
IPR034811 tPA
IPR001254 Trypsin_dom
IPR018114 TRYPSIN_HIS
IPR033116 TRYPSIN_SER
PANTHERiPTHR44617 PTHR44617, 1 hit
PfamiView protein in Pfam
PF00008 EGF, 1 hit
PF00039 fn1, 1 hit
PF00051 Kringle, 2 hits
PF00089 Trypsin, 1 hit
PIRSFiPIRSF001145 Tissue_plasm_act, 1 hit
PRINTSiPR00722 CHYMOTRYPSIN
SMARTiView protein in SMART
SM00058 FN1, 1 hit
SM00130 KR, 2 hits
SM00020 Tryp_SPc, 1 hit
SUPFAMiSSF50494 SSF50494, 1 hit
SSF57440 SSF57440, 2 hits
PROSITEiView protein in 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

Sequences (4)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P00750-1) [UniParc]FASTAAdd to basket
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.

« Hide

        10         20         30         40         50
MDAMKRGLCC VLLLCGAVFV SPSQEIHARF RRGARSYQVI CRDEKTQMIY
60 70 80 90 100
QQHQSWLRPV LRSNRVEYCW CNSGRAQCHS VPVKSCSEPR CFNGGTCQQA
110 120 130 140 150
LYFSDFVCQC PEGFAGKCCE IDTRATCYED QGISYRGTWS TAESGAECTN
160 170 180 190 200
WNSSALAQKP YSGRRPDAIR LGLGNHNYCR NPDRDSKPWC YVFKAGKYSS
210 220 230 240 250
EFCSTPACSE GNSDCYFGNG SAYRGTHSLT ESGASCLPWN SMILIGKVYT
260 270 280 290 300
AQNPSAQALG LGKHNYCRNP DGDAKPWCHV LKNRRLTWEY CDVPSCSTCG
310 320 330 340 350
LRQYSQPQFR IKGGLFADIA SHPWQAAIFA KHRRSPGERF LCGGILISSC
360 370 380 390 400
WILSAAHCFQ ERFPPHHLTV ILGRTYRVVP GEEEQKFEVE KYIVHKEFDD
410 420 430 440 450
DTYDNDIALL QLKSDSSRCA QESSVVRTVC LPPADLQLPD WTECELSGYG
460 470 480 490 500
KHEALSPFYS ERLKEAHVRL YPSSRCTSQH LLNRTVTDNM LCAGDTRSGG
510 520 530 540 550
PQANLHDACQ GDSGGPLVCL NDGRMTLVGI ISWGLGCGQK DVPGVYTKVT
560
NYLDWIRDNM RP
Length:562
Mass (Da):62,917
Last modified:July 21, 1986 - v1
Checksum:iB7EC9B1A5E3FDC4D
GO
Isoform 2 (identifier: P00750-2) [UniParc]FASTAAdd to basket
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.
Show »
Length:291
Mass (Da):32,175
Checksum:i874E38C52F50FF5D
GO
Isoform 3 (identifier: P00750-3) [UniParc]FASTAAdd to basket

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

Note: No experimental confirmation available.
Show »
Length:516
Mass (Da):57,371
Checksum:iBAB31901FDC96800
GO
Isoform 4 (identifier: P00750-4) [UniParc]FASTAAdd to basket
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.
Show »
Length:395
Mass (Da):44,373
Checksum:i55BB9FB94F65DF4F
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti93N → T in AAB59510 (PubMed:6089198).Curated1
Sequence conflicti159 – 160KP → NA in CAA31489 (PubMed:2107528).Curated2
Sequence conflicti247K → N in AAO34406 (Ref. 9) Curated1
Sequence conflicti283N → S in AAH95403 (PubMed:15489334).Curated1
Sequence conflicti333 – 334RR → EE in AAK11956 (Ref. 8) Curated2
Sequence conflicti389V → C in AAK11956 (Ref. 8) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02018134A → D1 PublicationCorresponds to variant dbSNP:rs8178733Ensembl.1
Natural variantiVAR_038732136R → S1 PublicationCorresponds to variant dbSNP:rs8178747Ensembl.1
Natural variantiVAR_038733146A → T1 PublicationCorresponds to variant dbSNP:rs8178748Ensembl.1
Natural variantiVAR_011783164R → W1 PublicationCorresponds to variant dbSNP:rs2020921Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0280291 – 40MDAMK…SYQVI → MAS in isoform 4. 1 PublicationAdd BLAST40
Alternative sequenceiVSP_01595739 – 85VICRD…VPVKS → G in isoform 3. 2 PublicationsAdd BLAST47
Alternative sequenceiVSP_02803079 – 208Missing in isoform 4. 1 PublicationAdd BLAST130
Alternative sequenceiVSP_005411269 – 291NPDGD…TWEYC → TGRSVSSPATASMRPCPLSI RSG in isoform 2. 1 PublicationAdd BLAST23
Alternative sequenceiVSP_005412292 – 562Missing in isoform 2. 1 PublicationAdd BLAST271

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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
CCDSiCCDS6126.1 [P00750-1]
CCDS6127.1 [P00750-3]
PIRiA94004 UKHUT
I38098
RefSeqiNP_000921.1, NM_000930.4 [P00750-1]
NP_001306118.1, NM_001319189.1
NP_127509.1, NM_033011.3 [P00750-3]
UniGeneiHs.491582

Genome annotation databases

EnsembliENST00000220809; ENSP00000220809; ENSG00000104368 [P00750-1]
ENST00000352041; ENSP00000270188; ENSG00000104368 [P00750-3]
ENST00000429089; ENSP00000392045; ENSG00000104368 [P00750-1]
GeneIDi5327
KEGGihsa:5327
UCSCiuc003xos.3 human [P00750-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiTPA_HUMAN
AccessioniPrimary (citable) accession number: P00750
Secondary accession number(s): A8K022
, B2R8E8, Q15103, Q503B0, Q6PJA5, Q7Z7N2, Q86YK8, Q9BU99, Q9BZW1
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 21, 1986
Last sequence update: July 21, 1986
Last modified: April 25, 2018
This is version 237 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Pharmaceutical, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health