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

More general terms

• serine protease inhibitor; serpin
• secreted protein
• glycoprotein

Additional terms

• 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)

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=5104
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:5104
• OMIM: https://mirror.omim.org/entry/601841
• UniProt: http://www.uniprot.org/uniprot/P05154.html