Plasminogen activator

Produced mainly in the liver, plasminogen is the inactive zymogen form of plasmin, and circulates in plasma in a closed conformation that cannot be activated. Binding clots or cell surface causes its conformation to change, allowing it to be activated by plasminogen activators. Plasminogen activators do so by cleaving the R561/V562 peptide bond, producing the active protein plasmin, which catalyzes the degradation of fibrin polymers that make up the structure of blood clots.[2]

3-dimensional structure of tPA

3-dimensional structure of uPA

The main inhibitor of tissue plasminogen activator and urokinase is plasminogen activator inhibitor-1 (PAI-1).[3] Plasminogen activator inhibitor-1 is a serine protease, synthesized by endothelial cells, that specifically inhibits tissue plasminogen activator (tPA) and urokinase (uPA). Tissue plasminogen activator and urokinase are the activators of plasminogen and results in the breakdown of blood clots (fibrinolysis).[4]

PAI-1 levels has also been studied in patients and how they influence certain diseases. Elevated serum levels of PAI-1 have been found in obese individuals.[5] Elevated levels of PAI-1 also seem to increase the risk of atherothrombotic events and may also promote vascular disease.[6]

Plasminogen activator inhibitor-2 (PAI-2) is also a serine protease that inactivates tPA and uPA. PAI-2 is produced by the placenta and only found in high quantities in the blood during pregnancy.[7]

Factor XIa and XIIa are two main factors involved in the plasminogen activator. Factor XI (FXI) is a serine protase produced by the liver and circulates in its inactive form.[8] Deficiency in factor XI is known to cause hemophilia C.[9] Factor XIIa is another plasma protein that is involved in the activation of zymogen factor is activated into factor XIa.[10] This activation is important to the coagulation cascade.

Due to its contribution to fibrinolysis, tissue plasminogen activator is used medically to treat blood clot-related disorders including thrombotic or embolic stroke, myocardial infarction, and pulmonary embolism. It is manufactured using recombinant techniques and is sold as alteplase, reteplase, and tenecteplase. Alteplase was the first of these versions to go on the market, and has the same exact structure as tPA. Reteplase and tenecteplase both received FDA approval after alteplase, and have nonidentical structures to tPA.[1] These recombinant forms of tPA have been shown to have a longer half-life in the blood and a greater resistance to inhibition, resulting in an increased capacity to treat thrombolytic diseases.[11]

Urokinase is similarly used in the medical field, specifically for the treatment of pulmonary embolism.[12]

PLG
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1B2I, 1BML, 1BUI, 1CEA, 1CEB, 1DDJ, 1HPJ, 1HPK, 1I5K, 1KI0, 1KRN, 1L4D, 1L4Z, 1PK4, 1PKR, 1PMK, 1QRZ, 1RJX, 2DOH, 2DOI, 2KNF, 2L0S, 2PK4, 3UIR, 4A5T, 4CIK, 4DCB, 4DUR, 4DUU, 5HPG
Identifiers
Aliases	PLG, plasminogen, plasmin, HAE4
External IDs	OMIM: 173350 MGI: 97620 HomoloGene: 55452 GeneCards: PLG
Gene location (Human) Chr. Chromosome 6 (human)[13] Band 6q26 Start 160,702,238 bp[13] End 160,754,097 bp[13]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[14] Band 17 A1|17 8.5 cM Start 12,597,495 bp[14] End 12,638,272 bp[14]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver kidney kidney tubule metanephric glomerulus ascending aorta tibial nerve right coronary artery left coronary artery popliteal artery right uterine tube Top expressed in left lobe of liver gallbladder yolk sac sexually immature organism abdominal wall primitive streak thoracic diaphragm ureter atrioventricular valve semi-lunar valve More reference expression data BioGPS More reference expression data
Gene ontology Molecular function apolipoprotein binding protein domain specific binding peptidase activity protein binding serine-type peptidase activity signaling receptor binding hydrolase activity serine-type endopeptidase activity chaperone binding proteasome core complex binding protein antigen binding endopeptidase activity enzyme binding kinase binding Cellular component blood microparticle extracellular region cell surface extrinsic component of external side of plasma membrane extracellular exosome platelet alpha granule lumen extracellular space plasma membrane extrinsic component of plasma membrane intracellular membrane-bounded organelle collagen-containing extracellular matrix Biological process hemostasis negative regulation of cell-substrate adhesion negative regulation of fibrinolysis negative regulation of cell-cell adhesion mediated by cadherin platelet degranulation extracellular matrix disassembly positive regulation of fibrinolysis tissue remodeling negative regulation of cell population proliferation blood coagulation proteolysis fibrinolysis positive regulation of blood vessel endothelial cell migration tissue regeneration myoblast differentiation muscle cell cellular homeostasis proteolysis involved in cellular protein catabolic process trophoblast giant cell differentiation labyrinthine layer blood vessel development mononuclear cell migration Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5340 18815 Ensembl ENSG00000122194 ENSMUSG00000059481 UniProt P00747 P20918 RefSeq (mRNA) NM_001168338 NM_000301 NM_008877 RefSeq (protein) NP_000292 NP_001161810 NP_032903 Location (UCSC) Chr 6: 160.7 – 160.75 Mb Chr 17: 12.6 – 12.64 Mb PubMed search [15] [16]
Wikidata
View/Edit Human View/Edit Mouse

Plasminogen activator inhibitor-1 not only functions as an inhibitor, but other roles of PAI-1 could suggest it could contribute to cancer. The other roles of PAI-1 include, cell de-adhesion, cell proliferation, apoptosis, and cell signaling. These roles could suggest that PAI-1 expression in the tumor microenvironment enhances tumor cell progression. Urokinase cleaves the zymogen plasminogen into serine protease plasmin. The elevated levels of uPA is an indicator of cancer which could be found in the carcinoma of the breast. Plasmin can activate matrix metalloproteases (MMP's) in the extracellular matrix (ECM). MMP activation contributes to tumor cell invasion and metastasis by degradation of ECM components.[5]

• Overview of all the structural information available in the PDB for UniProt: P00747 (Plasminogen) at the PDBe-KB.