Protein Variants | Comment | Organism |
---|---|---|
D167F/D172G | at saturating Ca2+ concentrations, the activation rates of the mutant and wild-type protein C by the thrombin-TM complex are comparable, but the mutant requires four-fold higher Ca2+ concentrations than wild-type APC to achieve half-maximal activation rates. When only thrombin is present, Ca2+ is not able to influence the activation of the D167F/D172G mutant, though Ca2+ effectively inhibits activation of wild-type protein C by thrombin | Homo sapiens |
E149A | the cytoprotective effects of the APC mutant are severely diminished, despite a normal cleavage of PAR-1 and normal binding to EPCR. E149A-APC expresses only 6% of the anti-apoptotic activity of wild-type APC in a staurosporine-induced apoptosis model in endothelial cells and was unable to down-regulate IL-6 release in lipopolysaccharide treated U937 monocytes | Homo sapiens |
E20A/V34M | the mutation is associated with thrombotic complications, despite the fact that carriers of these mutations have normal protein C antigen levels and APC amidolytic activity | Homo sapiens |
E357Q | E357 is involved in binding of macromolecular substrates. Engineered E357Q-APC shows two to threefold improved FVa inactivation, but slightly reduced anticoagulant activity in plasma compared to wild-type APC | Homo sapiens |
E7D | the mutation is associated with thrombotic complications, despite the fact that carriers of these mutations have normal protein C antigen levels and APC amidolytic activity | Homo sapiens |
K174E | site-directed mutagenesis, the activation rate of the mutant by thrombin is 12fold faster than that observed for wild-type protein C in the presence of Ca2+, and unchanged in the absence of Ca2+. Thrombin does not stimulate activation of the protein C variant | Homo sapiens |
L8Q | mutant variants L8Q and R9H show reduced affinity for EPCR and can contribute to the reduced anticoagulant activity | Homo sapiens |
additional information | single mutations of Gla domnain residues at positions 6, 7, 16, 20, 26 or 29 result in APC variants with less than 10% of the anticoagulant activity of wild-type APC | Homo sapiens |
P168V | at saturating Ca2+ concentrations, the activation rates of the mutant and wild-type protein C by the thrombin-TM complex are comparable, but the mutant requires four-fold higher Ca2+ concentrations than wild-type APC to achieve half-maximal activation rates. When only thrombin is present, Ca2+ is not able to influence the activation of the P168V mutant, though Ca2+ effectively inhibits activation of wild-type protein C by thrombin | Homo sapiens |
R15G | the mutation leads to increased thrombotic tendency | Homo sapiens |
R15W | the mutation leads to increased thrombotic tendency | Homo sapiens |
R177E | site-directed mutagenesis, the activation rate of the mutant by thrombin is 12fold faster than that observed for wild-type protein C in the presence of Ca2+, and unchanged in the absence of Ca2+. Thrombin does not stimulate activation of the protein C variant | Homo sapiens |
R178E | site-directed mutagenesis, the activation rate of the mutant by thrombin is 12fold faster than that observed for wild-type protein C in the presence of Ca2+, and unchanged in the absence of Ca2+. Thrombin does not stimulate activation of the protein C variant | Homo sapiens |
R9H | mutant variants L8Q and R9H show reduced affinity for EPCR and can contribute to the reduced anticoagulant activity | Homo sapiens |
Localization | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
extracellular | - |
Homo sapiens | - |
- |
Metals/Ions | Comment | Organism | Structure |
---|---|---|---|
Ca2+ | a group of four or five divalent cation binding sites in the Gla-domain show a high specificity for Ca2+. Ca2+ interactions are essential for the anticoagulant functions of APC and are influenced by mutations in different regions of the Gla-domain | Homo sapiens |
Molecular Weight [Da] | Molecular Weight Maximum [Da] | Comment | Organism |
---|---|---|---|
62000 | - |
x * 62000 | Homo sapiens |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
Factor Va + H2O | Homo sapiens | APC can inactivate FVa by proteolysis of three different peptide bonds at positions R306, R506 and R679. The cleavage at R506 is kinetically favoured, protein S-independent and yields a FVa intermediate with decreased factor Xa-cofactor activity. The slower cleavage at R306 is stimulated by protein S and completely inactivates FVa | ? | - |
? | |
factor VIII + H2O | Homo sapiens | - |
? | - |
? | |
additional information | Homo sapiens | function relationships of APC, overview | ? | - |
? |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | - |
- |
- |
Posttranslational Modification | Comment | Organism |
---|---|---|
proteolytic modification | protein C circulates in plasma as an inactive zymogen and is activated by thrombin bound to the endothelium associated transmembrane receptor thrombomodulin, that removes the 158-169 activation peptide of protein C via cleavage at R169, thus generating activated protein C, APC | Homo sapiens |
Source Tissue | Comment | Organism | Textmining |
---|---|---|---|
blood plasma | protein C circulates in plasma as an inactive zymogen and is activated by thrombin bound to the endothelium associated transmembrane receptor thrombomodulin | Homo sapiens | - |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
Factor Va + H2O | - |
Homo sapiens | ? | - |
? | |
Factor Va + H2O | APC can inactivate FVa by proteolysis of three different peptide bonds at positions R306, R506 and R679. The cleavage at R506 is kinetically favoured, protein S-independent and yields a FVa intermediate with decreased factor Xa-cofactor activity. The slower cleavage at R306 is stimulated by protein S and completely inactivates FVa | Homo sapiens | ? | - |
? | |
factor VIII + H2O | - |
Homo sapiens | ? | - |
? | |
additional information | function relationships of APC, overview | Homo sapiens | ? | - |
? |
Subunits | Comment | Organism |
---|---|---|
? | x * 62000 | Homo sapiens |
More | mapping of APC interactions on its overall 3D structure, overview. The N-terminal Gla-domain, residues 1-45, confers protein C its membrane and EPCR binding capacity and contributes to the binding between APC and protein S, three-dimensional Gla domain structure, overview | Homo sapiens |
Synonyms | Comment | Organism |
---|---|---|
Activated protein C | - |
Homo sapiens |
APC | - |
Homo sapiens |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
additional information | presence of the APC cofactor, protein S, thrombomodulin, endothelial protein C receptor and a phospholipid surface are important for the expression of anticoagulant APC activity, mechanism, overview | Homo sapiens | |
vitamin K | dependent on | Homo sapiens |
Organism | Comment | Expression |
---|---|---|
Homo sapiens | presence of the APC cofactor, protein S, thrombomodulin, endothelial protein C receptor and a phospholipid surface are important for the expression of anticoagulant APC activity | up |
General Information | Comment | Organism |
---|---|---|
additional information | function relationships of APC, overview. Presence of the APC cofactor, protein S, thrombomodulin, endothelial protein C receptor and a phospholipid surface are important for the expression of anticoagulant APC activity. Two or three cation binding-sites in the Gla-domain are occupied, resulting in a conformational change of the Gla-domain. Second, a group of four or five divalent cation binding sites with a high specificity for Ca2+ become occupied, enabling binding of the protein to acidic phosphalipid vesicles. Ca2+ interactions are essential for the anticoagulant functions of APC and are influenced by mutations in different regions of the Gla-domain. Residues R15, C22 and Gla-residues 6, 7, 16, 20, 25, 26 and 29 are thus absolutely required for APCs anticoagulant function | Homo sapiens |
physiological function | protein C is the central enzyme of the natural anticoagulant pathway, its activated form activated protein C is able to proteolyse non-active as well as active coagulation factors V and VIII in a protein S and factor V dependent manner, mechanism, overview. Proteolysis renders these cofactors inactive, resulting in an attenuation of thrombin formation and overall downregulation of coagulation. The activated enzyme also has direct cytoprotective effects on cells, since it is able to protect the endothelial barrier function and expresses anti-inflammatory and anti-apoptotic activities. Both the protease activated receptor 1 and EPCR are essential for the cytoprotective activity of APC. Also other receptors like sphingosine 1-phosphate receptor 1, Cd11b/CD18 and tyrosine kinase with immunoglobulin-like and EGFlike domains 2 are likewise important for APC signalling. The N-terminal Gla-domain, residues 1-45, confers protein C its membrane and EPCR binding capacity and contributes to the binding between APC and protein S, the C-terminus of the Gla-domain, residues 25-45, and particularly D35, D36, L38 and A39 were shown to interact with protein S | Homo sapiens |