ID:TPA_HUMAN DESCRIPTION: RecName: Full=Tissue-type plasminogen activator; Short=t-PA; Short=t-plasminogen activator; Short=tPA; EC=3.4.21.68; AltName: INN=Alteplase; AltName: INN=Reteplase; Contains: RecName: Full=Tissue-type plasminogen activator chain A; Contains: RecName: Full=Tissue-type plasminogen activator chain B; Flags: Precursor; 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. SUBUNIT: Heterodimer of chain A and chain B held by a disulfide bond. Forms 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. 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. DOMAIN: Both FN1 and EGF-like domains are important for binding to LRP1. DOMAIN: The FN1 domain mediates binding to annexin A2. DOMAIN: The second kringle domain is implicated in binding to cytokeratin-8 and to the endothelial cell surface binding site. PTM: 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. PTM: 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. PTM: N-glycosylation of Asn-152; the bound oligomannosidic glycan is involved in the interaction with the mannose receptor. PTM: Characterization of O-linked glycan was studied in Bowes melanoma cell line. DISEASE: Note=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: 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. SIMILARITY: Belongs to the peptidase S1 family. SIMILARITY: Contains 1 EGF-like domain. SIMILARITY: Contains 1 fibronectin type-I domain. SIMILARITY: Contains 2 kringle domains. SIMILARITY: Contains 1 peptidase S1 domain. WEB RESOURCE: Name=Wikipedia; Note=Tissue plasminogen activator entry; URL="http://en.wikipedia.org/wiki/Tissue_plasminogen_Activator"; WEB RESOURCE: Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/plat/"; WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and polymorphism database; URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=PLAT"; WEB RESOURCE: Name=Activase; Note=Clinical information on Activase; URL="http://www.gene.com/gene/products/information/cardiovascular/activase/insert.jsp#pharmacology"; WEB RESOURCE: Name=Retavase; Note=Clinical information on Retavase; URL="http://www.retavase.com/pdf/Retavase_PI.pdf";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P00750
Front
Top
Side
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.
Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
