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protein C inhibitor; plasma serine protease inhibitor; acrosomal serine protease inhibitor; plasminogen activator inhibitor 3; PAI-3; PAI3; PCI; Serpin A5 (SERPINA5, PCI, PLANH3, PROCI)

Function: - heparin-dependent serine protease inhibitor in body fluids & secretions - inactivates serine proteases by binding irreversibly to their serine activation site - role in regulation of intravascular & extravascular proteolysis - hemostatic roles in the blood plasma - acts as a procoagulant & 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 & fibrinolytic enzymes such as tissue-plasminogen activator & urinary-type plasminogen activators - in seminal fluid, inactivates several serine proteases implicated in reproduction - inhibits the serpin acrosin - indirectly protects component of the male genital tract from being degraded by excessive released acrosin - inhibits prostate-specific antigen & kallikrein - regulates sperm motility & fertilization - inhibits activated protein C-catalyzed degradation of SEMG1 & SEMG2 - regulates the degradation of semenogelin during transfer of spermatozoa from the male reproductive tract into the female tract - in urine, inhibits urinary-type plasminogen activator & kallikrein - inactivates membrane-anchored serine proteases activities such as MPRSS7 & TMPRSS11E - inhibits urinary-type plasminogen activator-dependent tumor cell invasion & metastasis - may also play a non-inhibitory role in seminal plasma & urine as an hydrophobic hormone carrier by its binding to retinoic acid - inhibitory activity is greatly enhanced in the presence of glycosaminoglycans, heparin, thrombomodulin & phospholipids - proteolytically cleaved - inhibition of proteases is accompanied by formation of a stable enzyme-inhibitor complex & by degradation of the serpin to lower molecular weight derivatives - proteolytically cleaved at the N-terminus - forms protease inhibiting heterodimers in extracellular body fluids with serine proteases such as activated protein C/ coagulation factor V/F5, acrosin/ACR, chymotrypsinogen B/CTRB1, prothrombin/F2, factor Xa/F10, factor XI/F11, kallikrein/KLKB1, tissue kallikrein, trypsin/PRSS1, prostate specific antigen/KLK3, tissue plasminogen activator/PLAT & urinary plasminogen activator/PLAU - forms protease inhibiting membrane-anchored heterodimers with TMPRSS7 & TMPRSS11E - interacts with SEMG2 Structure: - N-glycosylated & O-glycosylated - N-glycosylation consists of a mixture of sialylated bi- (including sialyl-Lewis X epitopes), tri- & tetra-antennary complex-type chains - affects the maximal heparin- & thrombomodulin-enhanced rates of thrombin inhibition - O- glycosylated with core 1 glycan or possibly core 8 glycan - further modified with 2 sialic acid residues - the reactive center loop (RCL) extends out from the body of the protein & directs binding to the target protease - the protease cleaves the serpin at the reactive site within the RCL, establishing a covalent linkage between the carboxyl group of the serpin reactive site & the serine hydroxyl of the protease - the resulting inactive serpin-protease complex is highly stable - belongs to the serpin family Compartment: - secreted, extracellular space - localized on plasma membrane overlying acrosomal head of spermatozoa of ependymal spermatozoa & ejaculated sperm - localized at the equatorial segment of acrosome-reacted spermatozoa - localized in alpha granules in resting platelets & on the external plasma membrane & within the surface-connected cannalicular system in activated platelets Expression: - predominantly expressed in epithelium of seminal vesicles - expressed in the proximal tubular epithelium of the kidney - expressed in the superficial & more differentiated epidermal keratinocytes of the skin - expressed in megakaryocytes & platelets - expressed poorly in kidney tumor cells compared to non tumor kidney tissues - expressed in spermatozoa - present in very high concentration in seminal plasma - present in high concentration in plasma, synovial & Graaf follicle fluids - present in low concentration in breast milk & in amniotic fluid - present in very low concentration in urine, CSF, saliva & tears - strongly expressed in liver - expressed in kidney, spleen, pancreas, skeletal muscle, heart, testes, ovary, interstitial Leydig cells, epididimal glands, seminal vesicles & prostate Notes: - relationship to tPA inhibitor unclear

protein C, activated protein C; vitamin K-dependent protein C; anticoagulant protein C; autoprothrombin IIA; blood coagulation factor XIV; contains: vitamin K-dependent protein C light chain; vitamin K-dependent protein C heavy chain; activation peptide (PROC)

General

glycoprotein secreted protein serine protease inhibitor; serpin

Properties

SIZE: entity length = 406 aa MW = 46 kD COMPARTMENT: extracellular compartment MOTIF: signal sequence {1-19} Thr glycosylation site {T39} N-glycosylation site {N249} N-glycosylation site {N262} N-glycosylation site {N338} peptide motif {373-374} INHIBITS: serine protease

Database Correlations

OMIM 601841 UniProt P05154 Pfam PF00079 Entrez Gene 5104 Kegg hsa:5104

References

UniProt :accession P05154
SeattleSNPs http://pga.gs.washington.edu/data/serpina5/