| Structural highlights
Function
[IPSP_HUMAN] Heparin-dependent serine protease inhibitor acting in body fluids and secretions. Inactivates serine proteases by binding irreversibly to their serine activation site. Involved in the regulation of intravascular and extravascular proteolytic activities. Plays hemostatic roles in the blood plasma. Acts as a procoagulant and proinflammatory factor by inhibiting the anticoagulant activated protein C factor as well as the generation of activated protein C factor by the thrombin/thrombomodulin complex. Acts as an anticoagulant factor by inhibiting blood coagulation factors like prothrombin, factor XI, factor Xa, plasma kallikrein and fibrinolytic enzymes such as tissue- and urinary-type plasminogen activators. In seminal plasma, inactivates several serine proteases implicated in the reproductive system. Inhibits the serpin acrosin; indirectly protects component of the male genital tract from being degraded by excessive released acrosin. Inhibits tissue-and urinary-type plasminogen activator, prostate-specific antigen and kallikrein activities; has a control on the sperm motility and fertilization. Inhibits the activated protein C-catalyzed degradation of SEMG1 and SEMG2; regulates the degradation of semenogelin during the process of transfer of spermatozoa from the male reproductive tract into the female tract. In urine, inhibits urinary-type plasminogen activator and kallikrein activities. Inactivates membrane-anchored serine proteases activities such as MPRSS7 and TMPRSS11E. Inhibits urinary-type plasminogen activator-dependent tumor cell invasion and metastasis. May also play a non-inhibitory role in seminal plasma and urine as a hydrophobic hormone carrier by its binding to retinoic acid.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Protein C inhibitor (PCI) is a multifunctional serpin with wide ranging protease inhibitory functions, unique cofactor binding activities, and potential non-inhibitory functions akin to the hormone-transporting serpins. To gain insight into the molecular mechanisms utilized by PCI we developed a robust expression system in Escherichia coli and solved the crystal structure of PCI in its native state. The five monomers obtained from our two crystal forms provide an NMR-like ensemble revealing regions of inherent flexibility. The reactive center loop (RCL) of PCI is long and highly flexible with no evidence of hinge region incorporation into beta-sheet A, as seen for other heparin-binding serpins. We adapted an extrinsic fluorescence method for determining dissociation constants for heparin and find that the N-terminal tail of PCI and residues adjacent to helix H are not involved in heparin binding. The minimal heparin length capable of tight binding to PCI was determined to be chains of eight monosaccharide units. A large hydrophobic pocket occupied by hydrophobic crystal contacts was found in an analogous position to the hormone-binding site in thyroxine-binding globulin. In conclusion, the data presented here provide important insights into the mechanisms by which PCI exercises its multiple inhibitory and non-inhibitory functions.
Structure of native protein C inhibitor provides insight into its multiple functions.,Li W, Adams TE, Kjellberg M, Stenflo J, Huntington JA J Biol Chem. 2007 May 4;282(18):13759-68. Epub 2007 Mar 2. PMID:17337440[19]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Suzuki K, Nishioka J, Kusumoto H, Hashimoto S. Mechanism of inhibition of activated protein C by protein C inhibitor. J Biochem. 1984 Jan;95(1):187-95. PMID:6323392
- ↑ Stief TW, Radtke KP, Heimburger N. Inhibition of urokinase by protein C-inhibitor (PCI). Evidence for identity of PCI and plasminogen activator inhibitor 3. Biol Chem Hoppe Seyler. 1987 Oct;368(10):1427-33. PMID:3501295
- ↑ Meijers JC, Kanters DH, Vlooswijk RA, van Erp HE, Hessing M, Bouma BN. Inactivation of human plasma kallikrein and factor XIa by protein C inhibitor. Biochemistry. 1988 Jun 14;27(12):4231-7. PMID:2844223
- ↑ Espana F, Gilabert J, Estelles A, Romeu A, Aznar J, Cabo A. Functionally active protein C inhibitor/plasminogen activator inhibitor-3 (PCI/PAI-3) is secreted in seminal vesicles, occurs at high concentrations in human seminal plasma and complexes with prostate-specific antigen. Thromb Res. 1991 Nov 1;64(3):309-20. PMID:1725227
- ↑ Zheng X, Geiger M, Ecke S, Bielek E, Donner P, Eberspacher U, Schleuning WD, Binder BR. Inhibition of acrosin by protein C inhibitor and localization of protein C inhibitor to spermatozoa. Am J Physiol. 1994 Aug;267(2 Pt 1):C466-72. PMID:7521127
- ↑ Cooper ST, Whinna HC, Jackson TP, Boyd JM, Church FC. Intermolecular interactions between protein C inhibitor and coagulation proteases. Biochemistry. 1995 Oct 10;34(40):12991-7. PMID:7548057
- ↑ Espana F, Fink E, Sanchez-Cuenca J, Gilabert J, Estelles A, Witzgall K. Complexes of tissue kallikrein with protein C inhibitor in human semen and urine. Eur J Biochem. 1995 Dec 1;234(2):641-9. PMID:8536714
- ↑ Kise H, Nishioka J, Kawamura J, Suzuki K. Characterization of semenogelin II and its molecular interaction with prostate-specific antigen and protein C inhibitor. Eur J Biochem. 1996 May 15;238(1):88-96. PMID:8665956
- ↑ Elisen MG, von dem Borne PA, Bouma BN, Meijers JC. Protein C inhibitor acts as a procoagulant by inhibiting the thrombomodulin-induced activation of protein C in human plasma. Blood. 1998 Mar 1;91(5):1542-7. PMID:9473218
- ↑ Elisen MG, van Kooij RJ, Nolte MA, Marquart JA, Lock TM, Bouma BN, Meijers JC. Protein C inhibitor may modulate human sperm-oocyte interactions. Biol Reprod. 1998 Mar;58(3):670-7. PMID:9510955
- ↑ Nishioka J, Ning M, Hayashi T, Suzuki K. Protein C inhibitor secreted from activated platelets efficiently inhibits activated protein C on phosphatidylethanolamine of platelet membrane and microvesicles. J Biol Chem. 1998 May 1;273(18):11281-7. PMID:9556620
- ↑ He S, Lin YL, Liu YX. Functionally inactive protein C inhibitor in seminal plasma may be associated with infertility. Mol Hum Reprod. 1999 Jun;5(6):513-9. PMID:10340997
- ↑ Jerabek I, Zechmeister-Machhart M, Binder BR, Geiger M. Binding of retinoic acid by the inhibitory serpin protein C inhibitor. Eur J Biochem. 2001 Nov;268(22):5989-96. PMID:11722589
- ↑ Wakita T, Hayashi T, Nishioka J, Tamaru H, Akita N, Asanuma K, Kamada H, Gabazza EC, Ido M, Kawamura J, Suzuki K. Regulation of carcinoma cell invasion by protein C inhibitor whose expression is decreased in renal cell carcinoma. Int J Cancer. 2004 Feb 10;108(4):516-23. PMID:14696115 doi:http://dx.doi.org/10.1002/ijc.11594
- ↑ Hobson JP, Netzel-Arnett S, Szabo R, Rehault SM, Church FC, Strickland DK, Lawrence DA, Antalis TM, Bugge TH. Mouse DESC1 is located within a cluster of seven DESC1-like genes and encodes a type II transmembrane serine protease that forms serpin inhibitory complexes. J Biol Chem. 2004 Nov 5;279(45):46981-94. Epub 2004 Aug 24. PMID:15328353 doi:http://dx.doi.org/10.1074/jbc.M403299200
- ↑ Hayashi T, Nishioka J, Kamada H, Asanuma K, Kondo H, Gabazza EC, Ido M, Suzuki K. Characterization of a novel human protein C inhibitor (PCI) gene transgenic mouse useful for studying the role of PCI in physiological and pathological conditions. J Thromb Haemost. 2004 Jun;2(6):949-61. PMID:15140131 doi:http://dx.doi.org/10.1111/j.1538-7836.2004.00733.x
- ↑ Szabo R, Netzel-Arnett S, Hobson JP, Antalis TM, Bugge TH. Matriptase-3 is a novel phylogenetically preserved membrane-anchored serine protease with broad serpin reactivity. Biochem J. 2005 Aug 15;390(Pt 1):231-42. PMID:15853774 doi:BJ20050299
- ↑ Sun W, Parry S, Panico M, Morris HR, Kjellberg M, Engstrom A, Dell A, Schedin-Weiss S. N-glycans and the N terminus of protein C inhibitor affect the cofactor-enhanced rates of thrombin inhibition. J Biol Chem. 2008 Jul 4;283(27):18601-11. doi: 10.1074/jbc.M800608200. Epub 2008 , May 8. PMID:18467335 doi:http://dx.doi.org/10.1074/jbc.M800608200
- ↑ Li W, Adams TE, Kjellberg M, Stenflo J, Huntington JA. Structure of native protein C inhibitor provides insight into its multiple functions. J Biol Chem. 2007 May 4;282(18):13759-68. Epub 2007 Mar 2. PMID:17337440 doi:10.1074/jbc.M701074200
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