Plasmin

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Plasminogen

PDB rendering based on 4dur.

Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes

Identifiers

Symbols PLG; DKFZp779M0222

External OMIM: 173350 MGI: 97620 IDs HomoloGene: 55452 GeneCards: PLG Gene

EC number

3.4.21.7

[show]Gene Ontology

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

Entrez

5340

18815

Ensembl ENSG00000122194 ENSMUSG00000059481

UniProt P00747

P20918

RefSeq (mRNA)

NM_000301.3

NM_008877.3

RefSeq (protein)

NP_000292.1

NP_032903.3

Location Chr 6: (UCSC) 161.12 161.17 Mb

Chr 17: 12.57 12.61 Mb

PubMed [1] search

[2]

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Plasmin is an important enzyme (EC 3.4.21.7) present in blood that degrades many blood plasma proteins, most notably, fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.[1]

Contents
[hide]

1 Function 2 Structure and mechanism of plasminogen activation to plasmin 3 Pathology 4 Interactions 5 References 6 Further reading

7 External links

[edit] Function

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 proteolyses proteins in various other systems: It activates collagenases, 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 proteases. 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 plasmingen 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 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.[1][2][3][4] Plasmin cleavage produces angiostatin.

[edit] Structure and mechanism of plasminogen activation to plasmin

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 .[4] 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.[4]

[edit] Pathology
Deficiency in plasmin may lead to thrombosis, as clots are not degraded adequately. Plasminogen deficiency in mice leads to defective liver repair,[5] defective wound healing, reproductive abnormalities.[citation needed] In human, a rare disorder called plasminogen deficiency type I (Online 'Mendelian Inheritance in Man' (OMIM) 217090) is caused by mutations of the PLG gene and is often manifested by ligneous conjunctivitis.

[edit] Interactions
Plasmin has been shown to interact with Thrombospondin 1,[6][7] Alpha 2-antiplasmin[8][9] and IGFBP3.[10]

[edit] References

1. ^ a b "Entrez Gene: plasminogen". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=53 40. 2. ^ Miyata T, Iwanaga S, Sakata Y, Aoki N (October 1982). "Plasminogen Tochigi: inactive plasmin resulting from replacement of alanine-600 by threonine in the active site". Proc. Natl. Acad. Sci. U.S.A. 79 (20): 61326. doi:10.1073/pnas.79.20.6132. PMC 347073. PMID 6216475. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=6216475. 3. ^ Forsgren M, Rden B, Israelsson M, Larsson K, Hedn LO (March 1987). "Molecular cloning and characterization of a full-length cDNA clone for human plasminogen". FEBS Lett. 213 (2): 25460. doi:10.1016/0014-5793(87)81501-6. PMID 3030813. http://linkinghub.elsevier.com/retrieve/pii/0014-5793(87)81501-6. 4. ^ a b c Law RHP, Caradoc-Davies T, Cowieson N, Horvath AJ, Quek AJ, Encarnacao JA, Steer D, Cowan A, Zhang Q, Lu BGC, Pike RN, Smith AI, Coughlin PB, Whisstock JC (2012). "The Xray Crystal Structure of Full-Length Human Plasminogen". Cell Reports 1 (3). doi:10.1016/j.celrep.2012.02.012. 5. ^ Jorge A. Bezerra, Thomas H. Bugge, Hector Melin-Aldana, Gregg Sabla, Keith W. Kombrinck, David P. Witte, and Jay L. Degen (December 21, 1999). Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver. Proceedings of the National Academy of Sciences of the United States of America. PMID 10611352. http://www.pnas.org/content/96/26/15143.short. Retrieved June 3, 2011. 6. ^ Silverstein, R L; Leung L L, Harpel P C, Nachman R L (Nov. 1984). "Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator". J. Clin. Invest. (UNITED STATES) 74 (5): 162533. doi:10.1172/JCI111578. ISSN 0021-9738. PMC 425339. PMID 6438154. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=425339. 7. ^ DePoli, P; Bacon-Baguley T, Kendra-Franczak S, Cederholm M T, Walz D A (Mar. 1989). "Thrombospondin interaction with plasminogen. Evidence for binding to a specific region of the kringle structure of plasminogen". Blood (UNITED STATES) 73 (4): 97682. ISSN 0006-4971. PMID 2522013. 8. ^ Wiman, B; Collen D (Sep. 1979). "On the mechanism of the reaction between human alpha 2antiplasmin and plasmin". J. Biol. Chem. (UNITED STATES) 254 (18): 92917. ISSN 00219258. PMID 158022. 9. ^ Shieh, B H; Travis J (May. 1987). "The reactive site of human alpha 2-antiplasmin". J. Biol. Chem. (UNITED STATES) 262 (13): 60559. ISSN 0021-9258. PMID 2437112. 10. ^ Campbell, P G; Durham S K, Suwanichkul A, Hayes J D, Powell D R (Aug. 1998). "Plasminogen binds the heparin-binding domain of insulin-like growth factor-binding protein-3". Am. J. Physiol. (UNITED STATES) 275 (2 Pt 1): E32131. ISSN 0002-9513. PMID 9688635.

[edit] 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". Proc. Natl. Acad. Sci. U.S.A. 102 (29): 101827. doi:10.1073/pnas.0501691102. PMC 1177369. PMID 16006527. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1177369. Angls-Cano E, Rojas G (2003). "Apolipoprotein(a): structure-function relationship at the lysinebinding site and plasminogen activator cleavage site". Biol. Chem. 383 (1): 939. doi:10.1515/BC.2002.009. PMID 11928826. Ranson M, Andronicos NM (2004). "Plasminogen binding and cancer: promises and pitfalls". Front. Biosci. 8: s294304. doi:10.2741/1044. PMID 12700073.

[edit] External links

The MEROPS online database for peptidases and their inhibitors: S01.233 MeSH Plasmin

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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PDB gallery

1b2i: KRINGLE 2 DOMAIN OF HUMAN PLASMINOGEN: NMR SOLUTION STRUCTURE OF TRANS-4AMINOMETHYLCYCLOHEXANE1-CARBOXYLIC ACID (AMCHA) COMPLEX

1bml: COMPLEX OF THE CATALYTIC DOMAIN OF HUMAN PLASMIN AND STREPTOKINASE

1bui: STRUCTURE OF THE TERNARY MICROPLASMINSTAPHYLOKINASEMICROPLASMIN COMPLEX: A PROTEINASE-COFACTORSUBSTRATE COMPLEX IN ACTION.

1cea: THE STRUCTURE OF THE NON-COVALENT COMPLEX OF RECOMBINANT KRINGLE 1 DOMAIN OF HUMAN PLASMINOGEN WITH EACA (EPSILONAMINOCAPROIC ACID)

1ceb: THE STRUCTURE OF THE NON-COVALENT COMPLEX OF RECOMBINANT KRINGLE 1 DOMAIN OF HUMAN PLASMINOGEN WITH AMCHA (TRANS-4AMINOMETHYLCYCLOHEXANE1-CARBOXYLIC ACID)

1ddj: CRYSTAL STRUCTURE OF HUMAN PLASMINOGEN CATALYTIC DOMAIN

1hpj: SOLUTION NMR STRUCTURE OF THE HUMAN PLASMINOGEN KRINGLE 1 DOMAIN COMPLEXED WITH 6AMINOHEXANOIC ACID AT PH 5.3, 310K, DERIVED FROM RANDOMLY GENERATED STRUCTURES USING SIMULATED ANNEALING, 12 STRUCTURES

1hpk: SOLUTION NMR STRUCTURE OF THE HUMAN PLASMINOGEN KRINGLE 1 DOMAIN COMPLEXED WITH 6AMINOHEXANOIC ACID AT PH 5.3, 310K, DERIVED FROM RANDOMLY GENERATED STRUCTURES USING SIMULATED ANNEALING, MINIMIZED AVERAGE STRUCTURE

1i5k: STRUCTURE AND BINDING DETERMINANTS OF THE RECOMBINANT KRINGLE-2 DOMAIN OF HUMAN PLASMINOGEN TO AN INTERNAL PEPTIDE FROM A GROUP

A STREPTOCOCCAL SURFACE PROTEIN

1ki0: The X-ray Structure of Human Angiostatin

1krn: STRUCTURE OF KRINGLE 4 AT 4C TEMPERATURE AND 1.67 ANGSTROMS RESOLUTION

1l4d: CRYSTAL STRUCTURE OF MICROPLASMINOGENSTREPTOKINASE ALPHA DOMAIN COMPLEX

1l4z: X-RAY CRYSTAL STRUCTURE OF THE COMPLEX OF MICROPLASMINOGEN WITH ALPHA DOMAIN OF STREPTOKINASE IN THE PRESENCE CADMIUM IONS

1pk4: CRYSTAL AND MOLECULAR STRUCTURE OF HUMAN PLASMINOGEN KRINGLE 4 REFINED AT 1.9ANGSTROMS RESOLUTION

1pkr: THE STRUCTURE OF RECOMBINANT PLASMINOGEN KRINGLE 1 AND THE FIBRIN BINDING SITE

1pmk: KRINGLE-KRINGLE INTERACTIONS IN MULTIMER KRINGLE STRUCTURES

1qrz: CATALYTIC DOMAIN OF PLASMINOGEN

1rjx: Human PLASMINOGEN CATALYTIC DOMAIN, K698M MUTANT

2doh: The X-ray crystallographic structure of the angiogenesis inhibitor, angiostatin, bound a to a peptide from the group A streptococcal surface protein PAM

2doi: The X-ray crystallographic structure of the angiogenesis inhibitor, angiostatin, bound to a peptide from the group A streptococcus protein PAM

2pk4: THE REFINED STRUCTURE OF THE EPSILON-AMINOCAPROIC ACID COMPLEX OF HUMAN PLASMINOGEN KRINGLE

5hpg: STRUCTURE AND LIGAND DETERMINANTS OF THE RECOMBINANT KRINGLE 5 DOMAIN OF HUMAN PLASMINOGEN [show]

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Proteins: Globular proteins

Alpha globulins serpins: alpha-1 (Alpha 1-antichymotrypsin, Alpha 1-antitrypsin)

alpha-2 (Alpha 2-antiplasmin) Antithrombin (Heparin cofactor II) carrier proteins: alpha-1 (Transcortin) alpha-2 (Ceruloplasmin) Retinol binding protein other: alpha-1 (Orosomucoid) alpha-2 (alpha-2-Macroglobulin, Haptoglobin) carrier proteins: Sex hormone-binding globulin Transferrin Beta globulins other: Angiostatin Hemopexin Beta-2 microglobulin Factor H Plasminogen Properdin Fibronectin (Fetal fibronectin) Macroglobulin/Microglobulin Transcobalamin

Gamma globulin Immunoglobulins Other

Egg white Conalbumin Ovalbumin Avidin Serum albumin Human serum albumin Bovine serum albumin Prealbumin C-reactive protein Lactalbumin (Alpha-lactalbumin) Parvalbumin Other Ricin [show]

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Proteins: coagulation
vWF Primary hemostasis platelet membrane glycoproteins: Ib (A, B, IX) IIb/IIIa (IIb, IIIa) VI HMWK/Bradykinin Prekallikrein/Kallikrein XII "Hageman" XI IX VIII

Intrinsic pathway

Extrinsic pathway III "Tissue factor" VII X V II "(Pro)thrombin" I "Fibrin" Fibrinogen (FGA, FGG) Common pathway XIII

M: MYL

cell/phys (coag, heme, rbmg/mogr/tumr/hist, immu, gran), csfs sysi/epon, btst

drug (B1/2/3+5+6), btst, trns

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Endopeptidases: serine proteases/serine endopeptidases (EC 3.4.21)

B enzm (
o o o o o o o o o o o o o

1.1 2 3 4 5 6 7 8 10 11 13 14 15-18 )

2.1 (
o o o

2 3 4

o o o o

5 6 7 8 )

2.7.10 2.7.11-12 3.1 (

o o o o o o

2 3 4 5 6 7 )

3.1.3.48 3.4.21 (
o o o

22 23 24 )

4.1 (
o o

2 3

o o o

4 5 6 )

5.1 (
o o o o

2 3 4 99 )

6.1-3 (
o o

4 5-6 )

Retrieved from "http://en.wikipedia.org/w/index.php?title=Plasmin&oldid=481427466" Categories: Human proteins Acute phase proteins Fibrinolytic system EC 3.4.21 Hidden categories: All articles with unsourced statements Articles with unsourced statements from January 2009 Wikipedia articles incorporating text from the United States National Library of Medicine
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