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tissue-type plasminogen activator; t-PA; t-plasminogen activator; tPA (PLAT)

Function: 1) relatively fibrin-selective plasminogen activator - converts plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen - by controlling plasmin-mediated proteolysis, plays a role in tissue remodeling & degradation, in cell migration & many other physiopathological events - minimizes systemic lytic states - play a direct role in facilitating neuronal migration - inhibited by SERPINA5 - 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 1 (glycosylated at Asn-219) & type1 (not glycosylated at Asn-219) - the single chain type 1 glycoform is less readily converted into the two-chain form by plasmin, & the two-chain type 1 glycoform has a lower activity than the two-chain type 2 glycoform in the presence of fibrin - 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 - heterodimer of chain A & 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 & 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 & laminin - binds to mannose receptor & LRP1 leading to TPA clearance - interactions on endothelial cells & vascular smooth muscle cells lead to a 100-fold stimulation of plasminogen activation - binding to vascular smooth muscle cells reduces TPA inhibition by PAI-1 by 30-fold - binds LRP1B; binding is followed by internalization & degradation Structure: - both FN1 domains & one of the kringle domains are required for binding to fibrin - both FN1 domains & 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 & to the endothelial cell surface binding site - belongs to the peptidase S1 family - contains 1 EGF-like domain - contains 1 fibronectin type-1 domain (FN1 domain) - contains 2 kringle domains - contains 1 peptidase S1 domain Compartment: secreted, extracellular space Alternative splicing: - named isoforms=4 - at least 1 isoform may be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay Expression: - synthesized in numerous tissues (including tumors) & secreted into most extracellular body fluids, such as plasma, uterine fluid, saliva, gingival crevicular fluid, tears, seminal fluid, & milk Pathology: - 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 Pharmacology: - vailable under the names alteplase (Activase) (Genentech) & reteplase (Retavase) (Centocor & Roche) - reteplase (Retavase) is a fragment of TPA that contains kringle 2 & the protease domain - see recombinant tissue plasminogen activator

Interactions

molecular events

Specific

recombinant tissue plasminogen activator (TPA, t-PA, rt-PA,)

General

glycoprotein plasma protein plasminogen activator

Properties

SIZE: entity length = 562 aa MW = 63 kD COMPARTMENT: plasma MOTIF: signal sequence {1-22} fibronectin type I domain or F1 module {39-81} MOTIF: cysteine residue {C41} MODIFICATION: cysteine residue {C71} annexin A2 binding {42-52} cysteine residue {C69} MODIFICATION: cysteine residue {C78} cysteine residue {C71} MODIFICATION: cysteine residue {C41} cysteine residue {C78} MODIFICATION: cysteine residue {C69} EGF domain {82-120} MOTIF: cysteine residue {C86} MODIFICATION: cysteine residue {C97} cysteine residue {C91} MODIFICATION: cysteine residue {C108} Thr glycosylation site {T96} cysteine residue {C97} MODIFICATION: cysteine residue {C86} tyrosine residue {102} cysteine residue {C108} MODIFICATION: cysteine residue {C91} cysteine residue {C110} MODIFICATION: cysteine residue {C119} cysteine residue {C119} MODIFICATION: cysteine residue {C110} Kringle 1 {127-208} MOTIF: cysteine residue {C127} MODIFICATION: cysteine residue {C208} cysteine residue {C148} MODIFICATION: cysteine residue {C190} N-glycosylation site {N152} cysteine residue {C179} MODIFICATION: cysteine residue {C203} cysteine residue {C190} MODIFICATION: cysteine residue {C148} cysteine residue {C203} MODIFICATION: cysteine residue {C179} cysteine residue {C208} MODIFICATION: cysteine residue {C127} Kringle 2 {215-296} MOTIF: cysteine residue {C215} MODIFICATION: cysteine residue {C296} N-glycosylation site {N219} cysteine residue {C236} MODIFICATION: cysteine residue {C278} asparagine residue {253} cysteine residue {C267} MODIFICATION: cysteine residue {C291} cysteine residue {C278} MODIFICATION: cysteine residue {C236} cysteine residue {C291} MODIFICATION: cysteine residue {C267} cysteine residue {C296} MODIFICATION: cysteine residue {C215} cysteine residue {C299} MODIFICATION: cysteine residue {C-INTERCHAIN} S1 domain {311-561} MOTIF: cysteine residue {C342} MODIFICATION: cysteine residue {C358} cysteine residue {C350} MODIFICATION: cysteine residue {C419} histidine residue {H357} cysteine residue {C358} MODIFICATION: cysteine residue {C342} aspartate residue {D406} cysteine residue {C419} MODIFICATION: cysteine residue {C350} cysteine residue {C444} MODIFICATION: cysteine residue {C519} lysine residue {464} cysteine residue {C476} MODIFICATION: cysteine residue {C492} N-glycosylation site {N483} cysteine residue {C492} MODIFICATION: cysteine residue {C476} cysteine residue {C509} MODIFICATION: cysteine residue {C537} aspartate residue {512} serine residue {S513} cysteine residue {C519} MODIFICATION: cysteine residue {C444} cysteine residue {C537} MODIFICATION: cysteine residue {C509} SECRETED-BY: endothelial cell MISC-INFO: 1/2life 5 MIN CONCENTRATION 5-10 UG/L

Database Correlations

OMIM 173370 UniProt P00750 PFAM correlations Entrez Gene 5327 Kegg hsa:5327

References

  1. Clinical Diagnosis and Management by Laboratory Methods, 18th ed, J.B. Henry (ed), W.B. Saunders, Philadelphia, PA, 1991 pg 739
  2. Baron M, Norman DG, Campbell ID. Protein modules. Trends Biochem Sci. 1991 Jan;16(1):13-7. Review. PMID: 2053133
  3. Fibrinolysis, Thrombosis, & Hemostasis: Concepts, Perspectives, and Clinical Applications. S Sherry, Lea & Febiger, Philadelphia, 1992, pg 71
  4. UniProt :accession P00750
  5. Wikipedia; Note: Tissue plasminogen activator entry http://en.wikipedia.org/wiki/Tissue_plasminogen_activator
  6. SeattleSNPs http://pga.gs.washington.edu/data/plat/
  7. SHMPD; Singapore human mutation and polymorphism database http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=PLAT

Component-of

tPA/tPA inhibitor 1