Protein C inhibitor

In the beginning, protein C inhibitor(PCI) was originally identified in human plasma by Griffin and Marlar{{cite journal | vauthors = Marlar RA, Griffin JH | title = Deficiency of protein C inhibitor in combined factor V/VIII deficiency disease | journal = The Journal of Clinical Investigation | volume = 66 | issue = 5 | pages = 1186–9 | year = 1980 | pmid = 6253526 | pmc = 371561 | doi = 10.1172/JCI109952 }} and first isolation was performed by Suzuki et al.{{cite journal | vauthors = Suzuki K, Nishioka J, Hashimoto S | title = Protein C inhibitor. Purification from human plasma and characterization | journal = The Journal of Biological Chemistry | volume = 258 | issue = 1 | pages = 163–8 | year = 1983 | doi = 10.1016/S0021-9258(18)33235-6 | pmid = 6294098 | url = http://www.jbc.org/content/258/1/163.short | doi-access = free }} Protein C inhibitor (PCI) can be isolated from human plasma using an ordinary chromatographic procedure consisting of barium citrate adsorption, polyethylene glycol fractionation, DEAE-Sepharose CL-6B treatment, ammonium sulfate fractionation, dextran sulfate-agarose chromatography, gel filtration on ACA-44, and DEAE-Sephacel chromatography.{{cite journal | vauthors = Meijers JC, Chung DW | title = Organization of the gene coding for human protein C inhibitor (plasminogen activator inhibitor-3). Assignment of the gene to chromosome 14 | journal = The Journal of Biological Chemistry | volume = 266 | issue = 23 | pages = 15028–34 | date = August 1991 | doi = 10.1016/S0021-9258(18)98581-9 | pmid = 1714450 | url = https://www.jbc.org/content/266/23/15028 | doi-access = free }}

The structure (primary structure) of protein C inhibitor was deduced from its cDNA nucleotide sequence. The human Protein C inhibitor have 19 amino acid signal peptide.{{cite journal | vauthors = Suzuki K, Deyashiki Y, Nishioka J, Kurachi K, Akira M, Yamamoto S, Hashimoto S | title = Characterization of a cDNA for human protein C inhibitor. A new member of the plasma serine protease inhibitor superfamily | journal = The Journal of Biological Chemistry | volume = 262 | issue = 2 | pages = 611–6 | date = January 1987 | doi = 10.1016/S0021-9258(19)75827-X | pmid = 3027058 | url = http://www.jbc.org/content/262/2/611 | doi-access = free }}

The study of genomic DNA by restriction mapping, polymerase chain reaction analysis and DNA sequencing showed the gene being 11.5 kilobases in length, consisting of five exons separated by four introns. The genetic code of protein C inhibitor is similar to alpha 1-antitrypsin and alpha 1-antichymotrypsin.

The in vivo half time degradation of protein C inhibitor in plasma is found to be 23 hours, whereas the half time degradation of protein C inhibitor and protein C complex is 20 minutes.{{cite journal | last1 = Suzuki | first1 = K. | title=Protein C inhibitor (PAI-3): structure and multi-function | journal = Fibrinolysis and Proteolysis | date=1 March 2000 | volume = 14 | issue = 2 | pages = 133–145 | doi = 10.1054/fipr.2000.0063 }}

Protein C inhibitors have ability to inhibit protein C, thrombin and other enzymes that are stimulated by heparin. The heparin binding site of protein C inhibitor is from 264-283 region. Heparin enhances the rate of inhibition leading to the conformational change in the structure of Protein C and other proteases. The binding site of heparin is different for protein C inhibitor and other proteases Heparin regulates the protein C inhibitor (PCI) activity and furthermore its specificity in those system where there is presence of two or more target proteases.{{cite journal | vauthors = Geiger M, Zechmeister-Machhart M, Uhrin P, Hufnagl P, Ecke S, Priglinger U, Xu J, Zheng X, Binder BR | title = Protein C inhibitor (PCI) | journal = Immunopharmacology | volume = 32 | issue = 1–3 | pages = 53–6 | year = 1996 | pmid = 8796266 | doi = 10.1016/0162-3109(96)00013-6 }}

Protein C inhibitor interacts with lipid membrane subsequently leading to permeabilization of bacterial pathogen exerting the antimicrobial activity. Protein C inhibitor a potent antimicrobial agent that have ability to destroy the bacterial cell wall, causing death of the bacteria.{{cite journal | vauthors = Malmström E, Mörgelin M, Malmsten M, Johansson L, Norrby-Teglund A, Shannon O, Schmidtchen A, Meijers JC, Herwald H | title = Protein C inhibitor--a novel antimicrobial agent | journal = PLOS Pathogens | volume = 5 | issue = 12 | pages = e1000698 | date = December 2009 | pmid = 20019810 | doi = 10.1371/journal.ppat.1000698 | pmc=2788422 | doi-access = free }}

Protein C inhibitor significantly reduces fertilization by inhibiting both the binding and penetration of zona free hamster oocytes by human sperm. This effect of PCI is dose dependent as 0.04MicroM PCI inhibited 50% binding and penetration ability.{{cite journal | vauthors = España F, Navarro S, Medina P, Zorio E, Estellés A | title = The role of protein C inhibitor in human reproduction | journal = Seminars in Thrombosis and Hemostasis | volume = 33 | issue = 1 | pages = 41–5 | date = February 2007 | pmid = 17253188 | doi = 10.1055/s-2006-958460 | s2cid = 260317586 }}

PCI communicated by malignant cells smothers tumor invasion by hindering urokinase-sort plasminogen activator, and restrains tumor development and metastasis which is independent of its protease inhibitory activity.{{cite journal | vauthors = Akita N, Ma N, Okamoto T, Asanuma K, Yoshida K, Nishioka J, Shimaoka M, Suzuki K, Hayashi T | title = Host protein C inhibitor inhibits tumor growth, but promotes tumor metastasis, which is closely correlated with hypercoagulability | journal = Thrombosis Research | volume = 135 | issue = 6 | pages = 1203–8 | date = June 2015 | pmid = 25887633 | doi = 10.1016/j.thromres.2015.03.026 }}

Deficiency of protein C inhibitor in the human body may cause male infertility. Protein C inhibitor has a role in reproduction as it has ability to inhibit the sperm protease acrosin.{{cite journal | vauthors = Uhrin P, Dewerchin M, Hilpert M, Chrenek P, Schöfer C, Zechmeister-Machhart M, Krönke G, Vales A, Carmeliet P, Binder BR, Geiger M | title = Disruption of the protein C inhibitor gene results in impaired spermatogenesis and male infertility | journal = The Journal of Clinical Investigation | volume = 106 | issue = 12 | pages = 1531–9 | date = December 2000 | pmid = 11120760 | doi = 10.1172/JCI10768 | pmc=381472}} Large amounts of protein C inhibitor circulate in the male reproductive organ as a plasma protein. Either deficiency or the presence of inactive protein C inhibitor can lead to male caused infertility.{{cite journal | vauthors = He S, Lin YL, Liu YX | title = Functionally inactive protein C inhibitor in seminal plasma may be associated with infertility | journal = Molecular Human Reproduction | volume = 5 | issue = 6 | pages = 513–9 | date = June 1999 | pmid = 10340997 | doi = 10.1093/molehr/5.6.513 | doi-access = free }}

Protein C inhibitor has often been shown to interact with prostate specific antigen,{{cite journal | vauthors = Christensson A, Lilja H | title = Complex formation between protein C inhibitor and prostate-specific antigen in vitro and in human semen | journal = European Journal of Biochemistry | volume = 220 | issue = 1 | pages = 45–53 | date = February 1994 | pmid = 7509746 | doi = 10.1111/j.1432-1033.1994.tb18597.x }}{{cite journal | vauthors = Kise H, Nishioka J, Kawamura J, Suzuki K | title = Characterization of semenogelin II and its molecular interaction with prostate-specific antigen and protein C inhibitor | journal = European Journal of Biochemistry | volume = 238 | issue = 1 | pages = 88–96 | date = May 1996 | pmid = 8665956 | doi = 10.1111/j.1432-1033.1996.0088q.x | doi-access = free }} protein C{{cite journal | vauthors = España F, Berrettini M, Griffin JH | title = Purification and characterization of plasma protein C inhibitor | journal = Thrombosis Research | volume = 55 | issue = 3 | pages = 369–84 | date = August 1989 | pmid = 2551064 | doi = 10.1016/0049-3848(89)90069-8 }}{{cite journal | vauthors = Strandberg K, Kjellberg M, Erb EM, Persson U, Mosher DF, Villoutreix BO, Stenflo J | title = Activated protein C-protein C inhibitor complex formation: characterization of a neoepitope provides evidence for extensive insertion of the reactive center loop | journal = Biochemistry | volume = 39 | issue = 51 | pages = 15713–20 | date = December 2000 | pmid = 11123896 | doi = 10.1021/bi001640h }} and PLAU.{{cite journal | vauthors = Geiger M, Huber K, Wojta J, Stingl L, Espana F, Griffin JH, Binder BR | title = Complex formation between urokinase and plasma protein C inhibitor in vitro and in vivo | journal = Blood | volume = 74 | issue = 2 | pages = 722–8 | date = August 1989 | doi = 10.1182/blood.V74.2.722.722 | pmid = 2752144 | doi-access = free }}

• Serpins
• Activated protein C–protein C inhibitor

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• {{cite journal | vauthors = Suzuki K, Hayashi T | title = cis-elements required for expression of human protein C inhibitor gene in HepG2 cells and its androgen-dependent expression in rat reproductive organs | journal = Seminars in Thrombosis and Hemostasis | volume = 26 | issue = 1 | pages = 75–83 | year = 2000 | pmid = 10805286 | doi = 10.1055/s-2000-9807 | s2cid = 33322227 }}
• {{cite journal | vauthors = Yasuda T, Nadano D, Iida R, Tanaka Y, Nakanaga M, Kishi K | title = Discovery of a genetic polymorphism of human plasma protein C inhibitor (PCI): genetic survey utilizing isoelectric focusing followed by immunoblotting, immunological and biochemical characterization | journal = Human Genetics | volume = 89 | issue = 3 | pages = 265–9 | date = May 1992 | pmid = 1318261 | doi = 10.1007/BF00220537 | s2cid = 25291094 }}
• {{cite journal | vauthors = Kuhn LA, Griffin JH, Fisher CL, Greengard JS, Bouma BN, España F, Tainer JA | title = Elucidating the structural chemistry of glycosaminoglycan recognition by protein C inhibitor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 21 | pages = 8506–10 | date = November 1990 | pmid = 2172989 | pmc = 54985 | doi = 10.1073/pnas.87.21.8506 | bibcode = 1990PNAS...87.8506K | doi-access = free }}
• {{cite journal | vauthors = Meijers JC, Chung DW | title = Evidence for a glycine residue at position 316 in human protein C inhibitor | journal = Thrombosis Research | volume = 59 | issue = 2 | pages = 389–93 | date = July 1990 | pmid = 2173165 | doi = 10.1016/0049-3848(90)90142-Y }}
• {{cite journal | vauthors = Laurell M, Stenflo J | title = Protein C inhibitor from human plasma: characterization of native and cleaved inhibitor and demonstration of inhibitor complexes with plasma kallikrein | journal = Thrombosis and Haemostasis | volume = 62 | issue = 3 | pages = 885–91 | date = November 1989 | pmid = 2556811 | doi = 10.1055/s-0038-1651022| s2cid = 24773168 }}
• {{cite journal | vauthors = Geiger M, Huber K, Wojta J, Stingl L, Espana F, Griffin JH, Binder BR | title = Complex formation between urokinase and plasma protein C inhibitor in vitro and in vivo | journal = Blood | volume = 74 | issue = 2 | pages = 722–8 | date = August 1989 | doi = 10.1182/blood.V74.2.722.722 | pmid = 2752144 | doi-access = free }}
• {{cite journal | vauthors = Zheng X, Geiger M, Ecke S, Bielek E, Donner P, Eberspächer U, Schleuning WD, Binder BR | title = Inhibition of acrosin by protein C inhibitor and localization of protein C inhibitor to spermatozoa | journal = The American Journal of Physiology | volume = 267 | issue = 2 Pt 1 | pages = C466–72 | date = August 1994 | pmid = 7521127 | doi = 10.1152/ajpcell.1994.267.2.C466}}
• {{cite journal | vauthors = Radtke KP, Fernández JA, Greengard JS, Tang WW, Wilson CB, Loskutoff DJ, Scharrer I, Griffin JH | title = Protein C inhibitor is expressed in tubular cells of human kidney | journal = The Journal of Clinical Investigation | volume = 94 | issue = 5 | pages = 2117–24 | date = November 1994 | pmid = 7525654 | pmc = 294656 | doi = 10.1172/JCI117566 }}
• {{cite journal | vauthors = Hayashi S | title = Urinary protein C inhibitor binding region in the B beta-chain of human fibrinogen | journal = Blood Coagulation & Fibrinolysis | volume = 4 | issue = 6 | pages = 921–6 | date = December 1993 | pmid = 8148485 | doi = 10.1097/00001721-199304060-00009 | s2cid = 33601129 }}
• {{cite journal | vauthors = Hayashi T, Suzuki K | title = Gene organization of human protein C inhibitor, a member of SERPIN family proteins encoded in five exons | journal = International Journal of Hematology | volume = 58 | issue = 3 | pages = 213–24 | date = October 1993 | pmid = 8148499 }}
• {{cite journal | vauthors = Billingsley GD, Walter MA, Hammond GL, Cox DW | title = Physical mapping of four serpin genes: alpha 1-antitrypsin, alpha 1-antichymotrypsin, corticosteroid-binding globulin, and protein C inhibitor, within a 280-kb region on chromosome I4q32.1 | journal = American Journal of Human Genetics | volume = 52 | issue = 2 | pages = 343–53 | date = February 1993 | pmid = 8381582 | pmc = 1682208 }}
• {{cite journal | vauthors = Hayashi S, Yamada K | title = Binding of urinary protein C inhibitor to fibrin(ogen) and its binding mechanism | journal = Blood Coagulation & Fibrinolysis | volume = 4 | issue = 1 | pages = 153–8 | date = February 1993 | pmid = 8384496 | doi = 10.1097/00001721-199304010-00027 }}
• {{cite journal | vauthors = Moore A, Penfold LM, Johnson JL, Latchman DS, Moore HD | title = Human sperm-egg binding is inhibited by peptides corresponding to core region of an acrosomal serine protease inhibitor | journal = Molecular Reproduction and Development | volume = 34 | issue = 3 | pages = 280–91 | date = March 1993 | pmid = 8471250 | doi = 10.1002/mrd.1080340308 | s2cid = 20713477 }}
• {{cite journal | vauthors = Hayashi S, Wakizaka A | title = Urinary protein C inhibitor binding region in the A alpha-chain of human fibrinogen | journal = Blood Coagulation & Fibrinolysis | volume = 6 | issue = 5 | pages = 382–7 | date = July 1995 | pmid = 8589203 | doi = 10.1097/00001721-199507000-00003 }}

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• The MEROPS online database for peptidases and their inhibitors: [https://archive.today/20121223041231/http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=I04.004 I04.004]
• {{MeshName|Protein+C+inhibitor}}

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{{Serpins}}

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{{DEFAULTSORT:Protein C Inhibitor}}

Category:Serine protease inhibitors