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Structure
Activated protein C is a spheroid shaped molecule with both alpha helices and beta sheets. The protein contains similar domains to other vitamin K dependent coagulation proteins with a heavy and light chain connected by a di-sulfide bond. The light chain contains a Gla domain and 2 epidermal growth factor domains, while the heavy chain contains an activated peptide domain and a serine protease domain.
The Gla domain contains glutamic acids which are converted to y-carboxyglutamic acid by a Vitamin K dependent reaction. The y-carboxyglutamic acid enables the protein to bind to Ca2+ and undergo a conformational change that enables binding to a phospholipid bilayer.
The Epidermal Growth Factor Domains are referenced as EGF-1 and EGF-2, with EGF-1 being proximal to the c-terminal domain and EGF-2 being proximal to the n-terminal domain. Protein C has a heavy and light chain and a cleavage after EGF2 results in the formation of two polypeptides, with Gla, EGF1, and EGF2, forming the light chain.
The serine protease domain, is composed of Histidine 211, Aspartic Acid 257, and Serine 360. The serine protease domain is part of the heavy chain.
Other key structural features of the 3-Dimensional structure include a cluster of positive charges at the surface of activated protein c near the active site. These positive charges are thought to bind to substrates and inhibitors.
Mechanism
Activated Protein C is a serine protease and utilizes residues Aspartic Acid 257, Histidine 211, and Serine 360 to cleave factors FV and FVIII as well as their activated forms. Protein C has been shown to be a highly functional enzyme functioning in the presence of membrane bound and unbound substrate, while being resistant to a variety of inhibitors. Activate Protein C has been shown to cleave FV only in the presence of a phospholipid bilayer at Arg 306 first, followed by Arg 506, and then Arg 679 and Lys 994. Under these conditions cleavage at Arg 306 is insufficient for inactivation. Activated Protein C can also degrade FVa.......
Protein C functions best in the presence of a phospholipid bilayer and with its cofactor Protein S.
Related Proteins
In general, protein C has a high degree of homology to other vitamin k dependent serine proteases. These Gla domain containing proteins include but are not limited to blood coagulation proteins. Non-blood coagulation proteins include trypsin and chymotrypsin. Coagulation proteins with a high degree of homology include prothrombin, Factor VII, Factor IX, and Factor X. Protein S and Protein Z are also fairly homologous, but they are not serine proteases. Despite the similarity in structure, the enzymes retain a high degree of specificity for their substrates, perhaps due to the nonhomologous surface loops that are away from the substrate binding pocket.
Links to Available Structures
The Protein Data Bank has Human Acitvated Protein C - 1AUT
The Protein Data Bank has Human Activated Protein C complexed with PPACK - 3F6U
Interesting Facts
Copperhead snake venom is thought to contain protein c activators.
References and Notes
- ↑ Esmon CT. The regulation of natural anticoagulant pathways. Science. 1987 Mar 13;235(4794):1348-52. PMID:3029867
- ↑ Esmon CT. Molecular events that control the protein C anticoagulant pathway. Thromb Haemost. 1993 Jul 1;70(1):29-35. PMID:8236111
- ↑ Stenflo J. Structure-function relationships of epidermal growth factor modules in vitamin K-dependent clotting factors. Blood. 1991 Oct 1;78(7):1637-51. PMID:1912552
- ↑ Suzuki K, Stenflo J, Dahlback B, Teodorsson B. Inactivation of human coagulation factor V by activated protein C. J Biol Chem. 1983 Feb 10;258(3):1914-20. PMID:6687387
- ↑ Fay PJ, Smudzin TM, Walker FJ. Activated protein C-catalyzed inactivation of human factor VIII and factor VIIIa. Identification of cleavage sites and correlation of proteolysis with cofactor activity. J Biol Chem. 1991 Oct 25;266(30):20139-45. PMID:1939075
- ↑ Rezaie AR. Regulation of the protein C anticoagulant and antiinflammatory pathways. Curr Med Chem. 2010;17(19):2059-69. PMID:20423310
- ↑ Brummel-Ziedin K, Orfeo T, Jenny NS, Everse SJ, and Mann KG. Wintrobe's Clinical Hematology. (2004, 11th ed) Chapter 21. Lippincott Williams and Wilkins ISBN:0781736501
