Phospholipid surfaces regulate the delivery of substrate to tissue factor:VIIa and the removal of product

Blood Cells, Molecules & Diseases
James HathcockY Nemerson

Abstract

For many years, the essential role of tissue factor (TF) in coagulation and thrombogenesis has been recognized. The catalytic complex of TF and VIIa (TF:VIIa) is membrane-bound whereas its substrate, factor X (FX), is distributed between a phospholipid-bound fraction and one that is in true solution in 3-dimensional space. This complicates analytical solutions for the kinetic mechanisms describing this reaction because dimensionality must be preserved. We believe that, at the time of activation, FX is simultaneously bound to TF:VIIa and the phospholipid surface. The hydrolysis of a peptide bond activates FX and the product, Xa, is yet bound to the catalytic complex in a manner such that it must leave before a new molecule of X encounters the complex. This means that, in principle, the classically defined Vmax does not apply because on a surface, infinite substrate and its attendant infinite collision frequency do not apply. We show that increasing the lipid surface area available to each TF:VIIa increases the apparent k(cat) and that it approaches a maximum asymptotically, exhibiting a K(1/2) at a 40 nm lipid radius. Notably, this is of the same order as transient confinement zones that have been identified on the surface of li...Continue Reading

Citations

Jul 3, 2013·Molecular and Cellular Biochemistry·Emma SmithColin Longstaff
Jun 15, 2007·Journal of Thrombosis and Haemostasis : JTH·D M Monroe, N S Key
Jan 24, 2007·Analytical Biochemistry·Angelica Wikström, Johanna Deinum
Jan 4, 2007·The Journal of Biological Chemistry·Andrew W ShawJames H Morrissey

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