Editing Plasmin (section)

== Mechanism of plasminogen activation ==

Full length  plasminogen comprises seven domains.  In addition to a  C-terminal chymotrypsin-like serine protease domain, plasminogen contains an [[PAN domain|N-terminal Pan Apple domain (PAp)]] together with five [[Kringle domain|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 .<ref name="Law_2012"/> 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.{{citation needed|date=February 2019}}

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.<ref name="Law_2012"/>