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P00750

- TPA_HUMAN

UniProt

P00750 - TPA_HUMAN

Protein

Tissue-type plasminogen activator

Gene

PLAT

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 202 (01 Oct 2014)
      Sequence version 1 (21 Jul 1986)
      Previous versions | rss
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    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)LengthDescriptionGraphical viewFeature identifierActions
    Sitei102 – 1021Important for binding to LRP1
    Sitei253 – 2531Not glycosylated
    Active sitei357 – 3571Charge relay system
    Active sitei406 – 4061Charge relay system
    Sitei464 – 4641Important for single-chain activity
    Sitei512 – 5121Important for single-chain activity
    Active sitei513 – 5131Charge relay system

    GO - Molecular functioni

    1. protein binding Source: UniProtKB
    2. serine-type endopeptidase activity Source: BHF-UCL

    GO - Biological processi

    1. blood coagulation Source: Reactome
    2. cellular protein modification process Source: ProtInc
    3. fibrinolysis Source: Reactome
    4. negative regulation of proteolysis Source: BHF-UCL
    5. plasminogen activation Source: UniProtKB
    6. platelet-derived growth factor receptor signaling pathway Source: Ensembl
    7. positive regulation of ovulation Source: Ensembl
    8. proteolysis Source: ProtInc
    9. regulation of synaptic plasticity Source: Ensembl
    10. response to cAMP Source: Ensembl
    11. response to glucocorticoid Source: Ensembl
    12. response to hypoxia Source: Ensembl
    13. response to peptide hormone Source: Ensembl
    14. smooth muscle cell migration Source: Ensembl
    15. synaptic transmission, glutamatergic Source: Ensembl

    Keywords - Molecular functioni

    Hydrolase, Protease, Serine protease

    Keywords - Biological processi

    Plasminogen activation

    Enzyme and pathway databases

    BRENDAi3.4.21.68. 2681.
    ReactomeiREACT_16888. Signaling by PDGF.
    REACT_641. Dissolution of Fibrin Clot.

    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
    ProteomesiUP000005640: Chromosome 8

    Organism-specific databases

    HGNCiHGNC:9051. PLAT.

    Subcellular locationi

    GO - Cellular componenti

    1. apical part of cell Source: Ensembl
    2. cell surface Source: BHF-UCL
    3. cytoplasm Source: BHF-UCL
    4. extracellular region Source: Reactome
    5. extracellular space Source: UniProtKB-SubCell
    6. extracellular vesicular exosome Source: UniProt
    7. secretory granule Source: Ensembl
    8. synapse Source: Ensembl

    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.

    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

    PharmGKBiPA33381.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 22221 PublicationAdd
    BLAST
    Propeptidei23 – 32101 PublicationPRO_0000028348
    Propeptidei33 – 353Removed by plasmin1 PublicationPRO_0000028349
    Chaini36 – 562527Tissue-type plasminogen activatorPRO_0000028350Add
    BLAST
    Chaini36 – 310275Tissue-type plasminogen activator chain APRO_0000028351Add
    BLAST
    Chaini311 – 562252Tissue-type plasminogen activator chain BPRO_0000028352Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi41 ↔ 711 Publication
    Disulfide bondi69 ↔ 781 Publication
    Disulfide bondi86 ↔ 971 Publication
    Disulfide bondi91 ↔ 1081 Publication
    Glycosylationi96 – 961O-linked (Fuc)1 PublicationCAR_000029
    Disulfide bondi110 ↔ 1191 Publication
    Disulfide bondi127 ↔ 208By similarity
    Disulfide bondi148 ↔ 190By similarity
    Glycosylationi152 – 1521N-linked (GlcNAc...)
    Disulfide bondi179 ↔ 203By similarity
    Disulfide bondi215 ↔ 2961 Publication
    Glycosylationi219 – 2191N-linked (GlcNAc...); partialCAR_000030
    Disulfide bondi236 ↔ 2781 Publication
    Disulfide bondi267 ↔ 2911 Publication
    Disulfide bondi299 ↔ 430Interchain (between A and B chains)1 PublicationPROSITE-ProRule annotation
    Disulfide bondi342 ↔ 358By similarity
    Disulfide bondi350 ↔ 419By similarity
    Disulfide bondi444 ↔ 519By similarity
    Disulfide bondi476 ↔ 492By similarity
    Glycosylationi483 – 4831N-linked (GlcNAc...)CAR_000031
    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

    Keywords - PTMi

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

    Proteomic databases

    MaxQBiP00750.
    PaxDbiP00750.
    PRIDEiP00750.

    PTM databases

    PhosphoSiteiP00750.
    UniCarbKBiP00750.

    Miscellaneous databases

    PMAP-CutDBB2R8E8.

    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

    ArrayExpressiP00750.
    BgeeiP00750.
    GenevestigatoriP00750.

    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.

    Protein-protein interaction databases

    BioGridi111343. 19 interactions.
    IntActiP00750. 2 interactions.
    MINTiMINT-8309345.

    Structurei

    Secondary structure

    1
    562
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi41 – 433
    Beta strandi44 – 463
    Beta strandi48 – 503
    Beta strandi55 – 595
    Beta strandi61 – 644
    Beta strandi66 – 705
    Beta strandi72 – 743
    Beta strandi77 – 815
    Beta strandi83 – 853
    Beta strandi96 – 1049
    Beta strandi106 – 1094
    Beta strandi115 – 1184
    Beta strandi221 – 2233
    Beta strandi229 – 2335
    Helixi242 – 2443
    Beta strandi248 – 2503
    Beta strandi251 – 2533
    Helixi256 – 2594
    Beta strandi262 – 2643
    Beta strandi277 – 2826
    Beta strandi285 – 2917
    Beta strandi309 – 3113
    Beta strandi312 – 3165
    Helixi319 – 3213
    Beta strandi325 – 3317
    Beta strandi338 – 3469
    Beta strandi348 – 3547
    Helixi356 – 3594
    Helixi365 – 3673
    Beta strandi368 – 3736
    Beta strandi375 – 3795
    Beta strandi385 – 39410
    Turni400 – 4023
    Beta strandi408 – 4125
    Beta strandi415 – 4173
    Beta strandi424 – 4263
    Beta strandi443 – 4497
    Beta strandi451 – 4533
    Beta strandi464 – 4707
    Helixi473 – 4753
    Turni478 – 4836
    Beta strandi490 – 4945
    Beta strandi499 – 5013
    Beta strandi516 – 5216
    Beta strandi524 – 53310
    Beta strandi535 – 5384
    Beta strandi544 – 5485
    Helixi549 – 5524
    Helixi553 – 5597

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    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[»]
    ProteinModelPortaliP00750.
    SMRiP00750. Positions 36-562.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP00750.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini39 – 8143Fibronectin type-IPROSITE-ProRule annotationAdd
    BLAST
    Domaini82 – 12039EGF-likePROSITE-ProRule annotationAdd
    BLAST
    Domaini127 – 20882Kringle 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini215 – 29682Kringle 2PROSITE-ProRule annotationAdd
    BLAST
    Domaini311 – 561251Peptidase S1PROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni42 – 5211Important for binding to annexin A2Add
    BLAST

    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
    Contains 1 EGF-like domain.PROSITE-ProRule annotation
    Contains 1 fibronectin type-I domain.PROSITE-ProRule annotation
    Contains 2 kringle domains.PROSITE-ProRule annotation
    Contains 1 peptidase S1 domain.PROSITE-ProRule annotation

    Keywords - Domaini

    EGF-like domain, Kringle, Repeat, Signal

    Phylogenomic databases

    eggNOGiCOG5640.
    HOVERGENiHBG008633.
    InParanoidiP00750.
    KOiK01343.
    OMAiAHVRLYP.
    OrthoDBiEOG75B84T.
    PhylomeDBiP00750.
    TreeFamiTF329901.

    Family and domain databases

    Gene3Di2.40.20.10. 2 hits.
    InterProiIPR000742. 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]
    PfamiPF00008. EGF. 1 hit.
    PF00039. fn1. 1 hit.
    PF00051. Kringle. 2 hits.
    PF00089. Trypsin. 1 hit.
    [Graphical view]
    PIRSFiPIRSF001145. Tissue_plasm_act. 1 hit.
    PRINTSiPR00722. CHYMOTRYPSIN.
    SMARTiSM00181. EGF. 1 hit.
    SM00058. FN1. 1 hit.
    SM00130. KR. 2 hits.
    SM00020. Tryp_SPc. 1 hit.
    [Graphical view]
    SUPFAMiSSF50494. SSF50494. 1 hit.
    SSF57440. SSF57440. 2 hits.
    PROSITEiPS00022. 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]

    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. Align

    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

    MDAMKRGLCC VLLLCGAVFV SPSQEIHARF RRGARSYQVI CRDEKTQMIY    50
    QQHQSWLRPV LRSNRVEYCW CNSGRAQCHS VPVKSCSEPR CFNGGTCQQA 100
    LYFSDFVCQC PEGFAGKCCE IDTRATCYED QGISYRGTWS TAESGAECTN 150
    WNSSALAQKP YSGRRPDAIR LGLGNHNYCR NPDRDSKPWC YVFKAGKYSS 200
    EFCSTPACSE GNSDCYFGNG SAYRGTHSLT ESGASCLPWN SMILIGKVYT 250
    AQNPSAQALG LGKHNYCRNP DGDAKPWCHV LKNRRLTWEY CDVPSCSTCG 300
    LRQYSQPQFR IKGGLFADIA SHPWQAAIFA KHRRSPGERF LCGGILISSC 350
    WILSAAHCFQ ERFPPHHLTV ILGRTYRVVP GEEEQKFEVE KYIVHKEFDD 400
    DTYDNDIALL QLKSDSSRCA QESSVVRTVC LPPADLQLPD WTECELSGYG 450
    KHEALSPFYS ERLKEAHVRL YPSSRCTSQH LLNRTVTDNM LCAGDTRSGG 500
    PQANLHDACQ GDSGGPLVCL NDGRMTLVGI ISWGLGCGQK DVPGVYTKVT 550
    NYLDWIRDNM RP 562
    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)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti93 – 931N → T in AAB59510. (PubMed:6089198)Curated
    Sequence conflicti159 – 1602KP → NA in CAA31489. (PubMed:2107528)Curated
    Sequence conflicti247 – 2471K → N in AAO34406. 1 PublicationCurated
    Sequence conflicti283 – 2831N → S in AAH95403. (PubMed:15489334)Curated
    Sequence conflicti333 – 3342RR → EE in AAK11956. 1 PublicationCurated
    Sequence conflicti389 – 3891V → C in AAK11956. 1 PublicationCurated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti34 – 341A → D.1 Publication
    Corresponds to variant rs8178733 [ dbSNP | Ensembl ].
    VAR_020181
    Natural varianti136 – 1361R → S.1 Publication
    Corresponds to variant rs8178747 [ dbSNP | Ensembl ].
    VAR_038732
    Natural varianti146 – 1461A → T.1 Publication
    Corresponds to variant rs8178748 [ dbSNP | Ensembl ].
    VAR_038733
    Natural varianti164 – 1641R → W.1 Publication
    Corresponds to variant rs2020921 [ dbSNP | Ensembl ].
    VAR_011783

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 4040MDAMK…SYQVI → MAS in isoform 4. 1 PublicationVSP_028029Add
    BLAST
    Alternative sequencei39 – 8547VICRD…VPVKS → G in isoform 3. 2 PublicationsVSP_015957Add
    BLAST
    Alternative sequencei79 – 208130Missing in isoform 4. 1 PublicationVSP_028030Add
    BLAST
    Alternative sequencei269 – 29123NPDGD…TWEYC → TGRSVSSPATASMRPCPLSI RSG in isoform 2. 1 PublicationVSP_005411Add
    BLAST
    Alternative sequencei292 – 562271Missing in isoform 2. 1 PublicationVSP_005412Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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_000930.3. [P00750-1]
    NP_127509.1. NM_033011.2. [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.2. human. [P00750-1]
    uc003xot.2. human. [P00750-3]

    Polymorphism databases

    DMDMi137119.

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Web resourcesi

    Wikipedia

    Tissue plasminogen activator entry

    SeattleSNPs
    SHMPD

    The Singapore human mutation and polymorphism database

    Activase

    Clinical information on Activase

    Retavase

    Clinical information on Retavase

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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 .
    CCDSi CCDS6126.1. [P00750-1 ]
    CCDS6127.1. [P00750-3 ]
    PIRi A94004. UKHUT.
    I38098.
    RefSeqi NP_000921.1. NM_000930.3. [P00750-1 ]
    NP_127509.1. NM_033011.2. [P00750-3 ]
    UniGenei Hs.491582.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    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 [» ]
    ProteinModelPortali P00750.
    SMRi P00750. Positions 36-562.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 111343. 19 interactions.
    IntActi P00750. 2 interactions.
    MINTi MINT-8309345.

    Chemistry

    BindingDBi P00750.
    ChEMBLi CHEMBL1873.
    DrugBanki DB00009. Alteplase.
    DB00513. Aminocaproic Acid.
    DB00029. Anistreplase.
    DB01088. Iloprost.
    DB00015. Reteplase.
    DB00031. Tenecteplase.
    DB00302. Tranexamic Acid.
    DB00013. Urokinase.
    GuidetoPHARMACOLOGYi 2392.

    Protein family/group databases

    MEROPSi S01.232.

    PTM databases

    PhosphoSitei P00750.
    UniCarbKBi P00750.

    Polymorphism databases

    DMDMi 137119.

    Proteomic databases

    MaxQBi P00750.
    PaxDbi P00750.
    PRIDEi P00750.

    Protocols and materials databases

    DNASUi 5327.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000220809 ; ENSP00000220809 ; ENSG00000104368 . [P00750-1 ]
    ENST00000352041 ; ENSP00000270188 ; ENSG00000104368 . [P00750-3 ]
    ENST00000429089 ; ENSP00000392045 ; ENSG00000104368 . [P00750-1 ]
    GeneIDi 5327.
    KEGGi hsa:5327.
    UCSCi uc003xos.2. human. [P00750-1 ]
    uc003xot.2. human. [P00750-3 ]

    Organism-specific databases

    CTDi 5327.
    GeneCardsi GC08M042032.
    HGNCi HGNC:9051. PLAT.
    HPAi CAB009335.
    HPA003412.
    MIMi 173370. gene.
    neXtProti NX_P00750.
    PharmGKBi PA33381.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG5640.
    HOVERGENi HBG008633.
    InParanoidi P00750.
    KOi K01343.
    OMAi AHVRLYP.
    OrthoDBi EOG75B84T.
    PhylomeDBi P00750.
    TreeFami TF329901.

    Enzyme and pathway databases

    BRENDAi 3.4.21.68. 2681.
    Reactomei REACT_16888. Signaling by PDGF.
    REACT_641. Dissolution of Fibrin Clot.

    Miscellaneous databases

    ChiTaRSi PLAT. human.
    EvolutionaryTracei P00750.
    GeneWikii Tissue_plasminogen_activator.
    GenomeRNAii 5327.
    NextBioi 20622.
    PMAP-CutDB B2R8E8.
    PROi P00750.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P00750.
    Bgeei P00750.
    Genevestigatori P00750.

    Family and domain databases

    Gene3Di 2.40.20.10. 2 hits.
    InterProi 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 ]
    Pfami PF00008. EGF. 1 hit.
    PF00039. fn1. 1 hit.
    PF00051. Kringle. 2 hits.
    PF00089. Trypsin. 1 hit.
    [Graphical view ]
    PIRSFi PIRSF001145. Tissue_plasm_act. 1 hit.
    PRINTSi PR00722. CHYMOTRYPSIN.
    SMARTi SM00181. EGF. 1 hit.
    SM00058. FN1. 1 hit.
    SM00130. KR. 2 hits.
    SM00020. Tryp_SPc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF50494. SSF50494. 1 hit.
    SSF57440. SSF57440. 2 hits.
    PROSITEi 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 ]
    ProtoNeti Search...

    Publicationsi

    1. 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. 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 DOMAIN.
    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. 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.

    Entry informationi

    Entry nameiTPA_HUMAN
    AccessioniPrimary (citable) accession number: P00750
    Secondary accession number(s): A8K022
    , B2R8E8, Q15103, Q503B0, Q6PJA5, Q7Z7N2, Q86YK8, Q9BU99, Q9BZW1
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 21, 1986
    Last sequence update: July 21, 1986
    Last modified: October 1, 2014
    This is version 202 of the entry and version 1 of the sequence. [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

    Documents

    1. Human chromosome 8
      Human chromosome 8: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. Peptidase families
      Classification of peptidase families and list of entries
    7. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3