Role of activation of the coagulation factor VIII in interaction with vWf, phospholipid, and functioning within the factor Xase complex.
Blood coagulation factor VIII (fVIII) in its nonactivated form circulates in plasma in a complex with von Willebrand factor (vWf). Upon activation by thrombin- or factor Xa-mediated site-specific proteolysis, activated fVIII (fVIIIa) serves as a cofactor for factor IXa. This protein complex assembled on a phospholipid surface (factor Xase) activates factor X. This complex plays the key role in the intrinsic pathway of blood coagulation. We reviewed the molecular events triggered by fVIII activation, which are required for the assembly and functioning of the Xase complex, including fVIIIa dissociation from vWf and a significant increase of fVIII affinity for binding to the phospholipid surface. Both events are mediated by activation-related cleavage within fVIII light chain (LCh), releasing the 40 amino-acid N-terminal LCh peptide, which is followed by a conformational change within the C2 domain. The conformational change within LCh is also required for the optimal fVIII cofactor functioning within the factor Xase complex, exerted via fVIIIa interactions with phospholipid, factor IXa, and factor X. Since factor IXa not only stabilizes but also proteolytically inactivates fVIIIa within the factor Xase complex, the stability of the membrane-bound fVIIIa in the presence and absence of factor IXa is discussed. In conclusion, we outline some new possible directions of the research. One of them arises from the recently demonstrated ability of plasma lipoproteins to provide a phospholipid surface for the assembly of the factor Xase complex in vitro. This finding raises a possibility that lipoproteins participate in factor Xase functioning in vivo and suggests a direct link between elevated levels of lipoproteins associated with atherosclerosis and increased thrombogenicity associated with this disease.
Saenko
E L
EL
Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
Shima
M
M
Sarafanov
A G
AG
D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation; D005169:Factor VIII / Q000378:metabolism*; D005170:Factor X / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009363:Neoplasm Proteins; D010743:Phospholipids / Q000097:blood*; D011485:Protein Binding; D011487:Protein Conformation; D014841:von Willebrand Factor / Q000378:metabolism*
D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010743:Phospholipids; D014841:von Willebrand Factor; D005169:Factor VIII; D005170:Factor X; D003546:Cysteine Endopeptidases; C030910:cancer procoagulant