View source for Plasmin

{{Infobox_gene}}
'''Plasmin''' is an important [[enzyme]] ({{EC number|3.4.21.7}}) present in [[blood]] that degrades many [[blood plasma]] proteins, including [[fibrin]] [[thrombus|clots]]. The degradation of fibrin is termed [[fibrinolysis]].  In humans, the plasmin protein is encoded by the ''PLG'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: plasminogen | url =https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5340 | accessdate = }}</ref>

== Function ==

[[File:Fibrinolysis.png|thumb|left|300px|Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.]]

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

Plasmin is released as a [[zymogen]] called '''plasminogen''' (PLG) from the liver into the systemic circulation.  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 [[enzymes]], including [[tissue plasminogen activator]] (tPA), [[urokinase]] plasminogen activator (uPA), [[kallikrein]], and [[factor XII]] (Hageman factor). Fibrin is a cofactor for plasminogen activation by tissue plasminogen activator. [[urokinase receptor|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.<ref name="entrez"/><ref name="pmid6216475">{{cite journal | vauthors = Miyata T, Iwanaga S, Sakata Y, Aoki N | title = Plasminogen Tochigi: inactive plasmin resulting from replacement of alanine-600 by threonine in the active site | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 79 | issue = 20 | pages = 6132–6  | date = October 1982 | pmid = 6216475 | pmc = 347073 | doi = 10.1073/pnas.79.20.6132 | url = http://www.pnas.org/cgi/pmidlookup?view=long&pmid=6216475 | bibcode = 1982PNAS...79.6132M }}</ref><ref name="pmid">{{cite journal | vauthors = Forsgren M, Råden B, Israelsson M, Larsson K, Hedén LO | title = Molecular cloning and characterization of a full-length cDNA clone for human plasminogen | journal = FEBS Lett. | volume = 213 | issue = 2 | pages = 254–60  | date = March 1987 | pmid = 3030813 | doi = 10.1016/0014-5793(87)81501-6 | url = http://linkinghub.elsevier.com/retrieve/pii/0014-5793(87)81501-6 }}</ref><ref name=Law_2012>{{cite journal | vauthors = Law RH, Caradoc-Davies T, Cowieson N, Horvath AJ, Quek AJ, Encarnacao JA, Steer D, Cowan A, Zhang Q, Lu BG, Pike RN, Smith AI, Coughlin PB, Whisstock JC | title = The X-ray crystal structure of full-length human plasminogen | journal = Cell Rep | volume = 1 | issue = 3 | pages = 185–90 | year = 2012 | pmid = 22832192 | doi = 10.1016/j.celrep.2012.02.012 }}</ref>

Plasmin cleavage produces [[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 [[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.

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"/>

== Mechanism of plasmin inactivation ==


{{Unreferenced section|date=November 2016}} 

Plasmin is inactivated by proteins such as [[Alpha-2-Macroglobulin|α2-macroglobulin]] and [[Alpha_2-antiplasmin|α2-antiplasmin]]. The mechanism of plasmin inactivation involves the cleavage of an α2-macroglobulin at the bait region (a segment of the aM that is particularly susceptible to proteolytic cleavage) by plasmin. This initiates a conformational change such that the α2-macroglobulin collapses about the plasmin. In the resulting α2-macroglobulin-plasmin complex, the active site of plasmin is [[Steric_effects#Steric_hindrance|sterically]] shielded, thus substantially decreasing the plasmin's access to protein substrates. Two additional events occur as a consequence of bait region cleavage, namely (i) a h-cysteinyl-g-glutamyl thiol ester of the α2-macroglobulin becomes highly reactive and (ii) a major conformational change exposes a conserved COOH-terminal receptor binding domain. The exposure of this receptor binding domain allows the α2-macroglobulin protease complex to bind to clearance receptors and be removed from circulation.

== Pathology ==

Plasmin deficiency may lead to [[thrombosis]], as clots are not adequately degraded. Plasminogen deficiency in mice leads to defective liver repair,<ref>{{cite journal | vauthors = Bezerra JA, Bugge TH, Melin-Aldana H, Sabla G, Kombrinck KW, Witte DP, Degen JL | title = Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 26 | pages = 15143–8  | date = December 21, 1999 | pmid = 10611352 | pmc = 24787 | doi = 10.1073/pnas.96.26.15143 | url = http://www.pnas.org/content/96/26/15143.short | publisher = Proceedings of the National Academy of Sciences of the United States of America | bibcode = 1999PNAS...9615143B }}</ref> defective wound healing, reproductive abnormalities.{{Citation needed|date=January 2009}}

In humans, a rare disorder called [[plasminogen deficiency type I]] ({{OMIM|217090}}) is caused by mutations of the PLG gene and is often manifested by [[ligneous conjunctivitis]].

== Interactions ==

Plasmin has been shown to [[Protein-protein interaction|interact]] with [[Thrombospondin 1]],<ref name=pmid6438154>{{cite journal | vauthors = Silverstein RL, Leung LL, Harpel PC, Nachman RL | title = Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator | journal = J. Clin. Invest. | volume = 74 | issue = 5 | pages = 1625–33  | date = November 1984 | pmid = 6438154 | pmc = 425339 | doi = 10.1172/JCI111578 }}</ref><ref name=pmid2522013>{{cite journal | vauthors = DePoli P, Bacon-Baguley T, Kendra-Franczak S, Cederholm MT, Walz DA | title = Thrombospondin interaction with plasminogen. Evidence for binding to a specific region of the kringle structure of plasminogen | journal = Blood | volume = 73 | issue = 4 | pages = 976–82  | date = March 1989 | pmid = 2522013 }}</ref> [[Alpha 2-antiplasmin]]<ref name=pmid158022>{{cite journal | vauthors = Wiman B, Collen D | title = On the mechanism of the reaction between human alpha 2-antiplasmin and plasmin | journal = J. Biol. Chem. | volume = 254 | issue = 18 | pages = 9291–7  | date = September 1979 | pmid = 158022 }}</ref><ref name=pmid2437112>{{cite journal | vauthors = Shieh BH, Travis J | title = The reactive site of human alpha 2-antiplasmin | journal = J. Biol. Chem. | volume = 262 | issue = 13 | pages = 6055–9  | date = May 1987 | pmid = 2437112 }}</ref> and [[IGFBP3]].<ref name=pmid9688635>{{cite journal | vauthors = Campbell PG, Durham SK, Suwanichkul A, Hayes JD, Powell DR | title = Plasminogen binds the heparin-binding domain of insulin-like growth factor-binding protein-3 | journal = Am. J. Physiol. | volume = 275 | issue = 2 Pt 1 | pages = E321-31  | date = August 1998 | pmid = 9688635 }}</ref> Moreover, plasmin induces the generation of [[bradykinin]] in mice and humans through [[high molecular weight kininogen]] cleavage.<ref>{{cite journal | vauthors = Marcos-Contreras OA, Martinez de Lizarrondo S, Bardou I, Orset C, Pruvost M, Anfray A, Frigout Y, Hommet Y, Lebouvier L, Montaner J, Vivien D, Gauberti M | title = Hyperfibrinolysis increases blood brain barrier permeability by a plasmin and bradykinin-dependent mechanism | journal = Blood | date = August 2016 | pmid = 27531677 | doi = 10.1182/blood-2016-03-705384 | volume=128 | pages=2423–2434}}</ref>

== References ==
{{Reflist|33em}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Shanmukhappa K, Mourya R, Sabla GE, Degen JL, Bezerra JA | title = Hepatic to pancreatic switch defines a role for hemostatic factors in cellular plasticity in mice | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 102 | issue = 29 | pages = 10182–7  | date = July 2005 | pmid = 16006527 | pmc = 1177369 | doi = 10.1073/pnas.0501691102 | bibcode = 2005PNAS..10210182S }}
* {{cite journal | vauthors = Anglés-Cano E, Rojas G | title = Apolipoprotein(a): structure-function relationship at the lysine-binding site and plasminogen activator cleavage site | journal = Biol. Chem. | volume = 383 | issue = 1 | pages = 93–9 | year = 2002 | pmid = 11928826 | doi = 10.1515/BC.2002.009 }}
* {{cite journal | vauthors = Ranson M, Andronicos NM | title = Plasminogen binding and cancer: promises and pitfalls | journal = Front. Biosci. | volume = 8 | issue =  | pages = s294-304 | year = 2003 | pmid = 12700073 | doi = 10.2741/1044 }}
{{refend}}

== External links ==
*The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=S01.233 S01.233]
*{{MeshName|Plasmin}}

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[[Category:Acute phase proteins]]
[[Category:Fibrinolytic system]]
[[Category:EC 3.4.21]]
[[Category:Extracellular matrix remodeling enzymes]]