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- W4313886677 abstract "Polyphosphate (polyP) promotes feedback activation of factor (F) XI by thrombin by serving as a template. The contribution of thrombin's exosites to these interactions is unclear.To determine the contribution of thrombin exosites 1 and 2 to polyP-induced potentiation of FXI activation by thrombin.The affinities of α-thrombin; K109E/110E-thrombin, an exosite 1 variant, or R93E-thrombin, an exosite 2 variant; FXI; and FXIa for polyP-70 were quantified using surface plasmon resonance in the absence or presence of exosite ligands. FXI was activated with α-thrombin or thrombin variants in the absence or presence of polyP-70 and exosite ligands.α-Thrombin, K109/110E-thrombin, FXI, and FXIa bound polyP-70, whereas R93E-thrombin exhibited minimal binding. Exosite 1 and exosite 2 ligands attenuated thrombin binding to polyP-70. PolyP-70 accelerated the rate of FXI activation by α-thrombin and K109E/110E-thrombin but not R93E-thrombin up to 1500-fold in a bell-shaped, concentration-responsive manner. Exosite 1 and exosite 2 ligands had no impact on FXI activation by thrombin in the absence of polyP-70; however, in its presence, they attenuated activation by 40% to 65%.PolyP-70 binds FXI and thrombin and promotes their interaction. Exosite 2 ligands attenuate activation because thrombin binds polyP-70 via exosite 2. Attenuation of FXI activation by exosite 1 ligands likely reflects allosteric modulation of exosite 2 and/or the active site of thrombin because exosite 1 is not directly involved in FXI activation. Therefore, allosteric modulation of thrombin's exosites may represent a novel strategy for downregulating FXI activation." @default.
- W4313886677 created "2023-01-10" @default.
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- W4313886677 date "2023-01-01" @default.
- W4313886677 modified "2023-10-16" @default.
- W4313886677 title "Allosteric modulation of exosite 1 attenuates polyphosphate-catalyzed activation of factor XI by thrombin" @default.
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- W4313886677 doi "https://doi.org/10.1016/j.jtha.2022.10.001" @default.
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