Plasmin
Ensembl | |||||||||
---|---|---|---|---|---|---|---|---|---|
UniProt | |||||||||
RefSeq (mRNA) | |||||||||
RefSeq (protein) | |||||||||
Location (UCSC) | Chr 6: 160.7 – 160.75 Mb | Chr 17: 12.6 – 12.64 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Plasmin is an important enzyme (EC 3.4.21.7) present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encoded by the PLG gene.[5]
Function
Plasmin is a
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
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 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 .[9] 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]
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
Mechanism of plasmin inactivation
Plasmin is inactivated by proteins such as α2-macroglobulin and α2-antiplasmin.[10] 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 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 the clots are not adequately degraded. Plasminogen deficiency in mice leads to defective liver repair,[11] defective wound healing, reproductive abnormalities.[12] [13]
In humans, a rare disorder called
A rare missense mutation within the kringle 3 domain of plasminogen, resulting in a novel type of dysplasminogenemia, represents the molecular basis of a subtype of hereditary angioedema with normal C1-inhibitor;[15] the mutation creates a new lysine-binding site within kringle 3 and alters the glycosylation of plasminogen.[15] The mutant plasminogen protein has been shown to be a highly efficient kininogenase that directly releases bradykinin from high- and low-molecular-weight kininogen.[16]
Interactions
Plasmin has been shown to interact with Thrombospondin 1,[17][18] Alpha 2-antiplasmin[19][20] and IGFBP3.[21] Moreover, plasmin induces the generation of bradykinin in mice and humans through high-molecular-weight kininogen cleavage.[22]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000122194 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000059481 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: plasminogen".
- PMID 32594031.
- PMID 6216475.
- S2CID 9075872.
- ^ PMID 22832192.
- S2CID 73463150.
- PMID 10611352.
- S2CID 29981847.
- PMID 7586361.
- PMID 17900274.
- ^ PMID 29548426.
- PMID 35100351.
- PMID 6438154.
- PMID 2522013.
- PMID 158022.
- PMID 2437112.
- PMID 9688635.
- PMID 27531677.
Further reading
- Shanmukhappa K, Mourya R, Sabla GE, Degen JL, Bezerra JA (July 2005). "Hepatic to pancreatic switch defines a role for hemostatic factors in cellular plasticity in mice". Proceedings of the National Academy of Sciences of the United States of America. 102 (29): 10182–10187. PMID 16006527.
- Anglés-Cano E, Rojas G (January 2002). "Apolipoprotein(a): structure-function relationship at the lysine-binding site and plasminogen activator cleavage site". Biological Chemistry. 383 (1): 93–99. S2CID 29248198.
- Ranson M, Andronicos NM (May 2003). "Plasminogen binding and cancer: promises and pitfalls". Frontiers in Bioscience. 8 (6): s294–s304. PMID 12700073.
External links
- The MEROPS online database for peptidases and their inhibitors: S01.233 Archived 2019-09-13 at the Wayback Machine
- Plasmin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.