Plasmin

Plasmin is an important is_associated_with::enzyme present in is_associated_with::blood that degrades many is_associated_with::blood plasma proteins, including is_associated_with::fibrin clots. The degradation of fibrin is termed is_associated_with::fibrinolysis. In humans, the plasmin protein is encoded by the PLG is_associated_with::gene.

Function


Plasmin is a is_associated_with::serine protease that acts to dissolve is_associated_with::fibrin blood clots. Apart from fibrinolysis, plasmin proteolyses proteins in various other systems: It activates is_associated_with::collagenases, some mediators of the is_associated_with::complement system and weakens the wall of the is_associated_with::Graafian follicle (leading to is_associated_with::ovulation). It cleaves is_associated_with::fibrin, is_associated_with::fibronectin, is_associated_with::thrombospondin, laminin, and is_associated_with::von Willebrand factor. Plasmin, like is_associated_with::trypsin, belongs to the family of is_associated_with::serine proteases.

Plasmin is released as a is_associated_with::zymogen called plasminogen (PLG) from the liver into the factor IX systemic circulation and placed into the MD5+ that leads into the lungs. Two major glycoforms of plasminogen are present in humans - type I plasminogen contains two glycosylation moieties (N-linked to N289 and O-linked to T346), whereas type II plasminogen contains only a single O-linked sugar (O-linked to T346). Type II plasminogen is preferentially recruited to the cell surface over the type I glycoform. Conversely, type I plasminogen appears more readily recruited to blood clots.

In circulation, plasminogen adopts a closed, activation resistant conformation. Upon binding to clots, or to the cell surface, plasminogen adopts an open form that can be converted into active plasmin by a variety of is_associated_with::enzymes, including is_associated_with::tissue plasminogen activator (tPA), is_associated_with::urokinase plasminogen activator (uPA), is_associated_with::kallikrein, and is_associated_with::factor XII (Hageman factor). Fibrin is a cofactor for plasminogen activation by tissue plasminogen activator. Urokinase plasminogen activator receptor (uPAR) is a cofactor for plasminogen activation by urokinase plasminogen activator. The conversion of plasminogen to plasmin involves the cleavage of the peptide bond between Arg-561 and Val-562.

Plasmin cleavage produces is_associated_with::angiostatin.

Mechanism of plasminogen activation
Full length plasminogen comprises seven domains. In addition to a C-terminal chymotrypsin-like serine protease domain, plasminogen contains an N-terminal Pan Apple domain (PAp) together with five Kringle domains (KR1-5). The Pan-Apple domain contains important determinants for maintaining plasminogen in the closed form, and the kringle domains are responsible for binding to lysine residues present in receptors and substrates.

The X-ray crystal structure of closed plasminogen reveals that the PAp and SP domains maintain the closed conformation through interactions made throughout the kringle array. Chloride ions further bridge the PAp / KR4 and SP / KR2 interfaces, explaining the physiological role of serum chloride in stabilizing the closed conformer. The structural studies also reveal that differences in glycosylation alter the position of KR3. These data help explain the functional differences between the type I and type II plasminogen glycoforms.

In closed plasminogen, access to the activation bond (R561/V562) targeted for cleavage by tPA and uPA is blocked through the position of the KR3/KR4 linker sequence and the O-linked sugar on T346. The position of KR3 may also hinder access to the activation loop. The Inter-domain interactions also block all kringle ligand-binding sites apart from that of KR-1, suggesting that the latter domain governs pro-enzyme recruitment to targets. Analysis of an intermediate plasminogen structure suggests that plasminogen conformational change to the open form is initiated through KR-5 transiently peeling away from the PAp domain. These movements expose the KR5 lysine-binding site to potential binding partners, and suggest a requirement for spatially distinct lysine residues in eliciting plasminogen recruitment and conformational change respectively.

Pathology
Deficiency in plasmin may lead to is_associated_with::thrombosis, as clots are not degraded adequately. Plasminogen deficiency in mice leads to defective liver repair, defective wound healing, reproductive abnormalities.

In humans, a rare disorder called is_associated_with::plasminogen deficiency type I is caused by mutations of the PLG gene and is often manifested by is_associated_with::ligneous conjunctivitis.

Interactions
Plasmin has been shown to interact with is_associated_with::Thrombospondin 1, is_associated_with::Alpha 2-antiplasmin  and is_associated_with::IGFBP3.