Literature summary for 3.4.21.69 extracted from

Wildhagen, K.C.; Lutgens, E.; Loubele, S.T.; Ten Cate, H.; Nicolaes, G.A.
The structure-function relationship of activated protein C. Lessons from natural and engineered mutations (2011), Thromb. Haemost., 106, 1034-1045.

Search for more literature for 3.4.21.69

Protein Variants

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

Localization	Comment	Organism	GeneOntology No.	Textmining
extracellular	-	Homo sapiens	-	-

Metals/Ions

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 [Da]	Molecular Weight Maximum [Da]	Comment	Organism
62000	-	x * 62000	Homo sapiens

Natural Substrates/ Products (Substrates)

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

Organism	UniProt	Comment	Textmining
Homo sapiens	-	-	-

Posttranslational Modification

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

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 and Products (Substrate)

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

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

Synonyms	Comment	Organism
Activated protein C	-	Homo sapiens
APC	-	Homo sapiens

Cofactor

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

Expression

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

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

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Release 2023.1 (January 2023)