Figure 1.
Figure 1. APC anticoagulant and cell signaling pathways and the structure of signaling-selective 3K3A-APC. (A) Anticoagulant activity of APC involves the proteolytic inactivation of factors Va and VIIIa on membrane surfaces containing phospholipids that are derived from cells, platelets, lipoproteins, or cellular microparticles. The irreversible inactivation of factors Va and VIIIa to yield inactive factors Vi and VIIIi by APC is accelerated by a variety of lipid and protein cofactors (eg, glucosyl ceramide, protein S, etc). (B) Beneficial direct effects of APC on cells require the EPCR and PAR1. One distinction between proinflammatory thrombin signaling and cytoprotective APC signaling is the localization of APC signaling in the caveolin-1–rich microdomains (caveolae). (C) Neuroprotective mechanisms for APC effects on cells may also involve other receptors including PAR-3. APC-initiated signaling effects on cells can include antiapoptotic activities, anti-inflammatory activities, inhibition of the inflammasome, stabilization of endothelial barrier functions including the BBB, and neurogenesis. (D) The polypeptide structure of APC comprises an N-terminal GLA domain (green) that binds to negatively charged lipids and EPCR, 2 EGF-like domains (blue), and the protease domain containing the active site triad of serine, histidine, and aspartic acid residues (red). Four glycosylation sites are indicated by gray-shaded moieties. Substrate selectivity of this protease is determined by interactions between the targeted substrates and the active site and also by multiple unique binding exosites on APC that vary for different substrates. The protease domain space–filled model (see insert) highlights in the yellow box 3 positively charged lysine (K) residues within the so-called 37 loop (KKK 191-193), which is an exosite for APC’s recognition of factors Va and VIIIa. Mutation of these 3 residues to alanine (3K3A-APC) reduces APC’s anticoagulant activity by >90%, but it does not affect its interactions with the cytoprotective substrates, PAR1, or its other known cell signaling receptors. Thus, 3K3A-APC is very signaling selective.

APC anticoagulant and cell signaling pathways and the structure of signaling-selective 3K3A-APC. (A) Anticoagulant activity of APC involves the proteolytic inactivation of factors Va and VIIIa on membrane surfaces containing phospholipids that are derived from cells, platelets, lipoproteins, or cellular microparticles. The irreversible inactivation of factors Va and VIIIa to yield inactive factors Vi and VIIIi by APC is accelerated by a variety of lipid and protein cofactors (eg, glucosyl ceramide, protein S, etc). (B) Beneficial direct effects of APC on cells require the EPCR and PAR1. One distinction between proinflammatory thrombin signaling and cytoprotective APC signaling is the localization of APC signaling in the caveolin-1–rich microdomains (caveolae). (C) Neuroprotective mechanisms for APC effects on cells may also involve other receptors including PAR-3. APC-initiated signaling effects on cells can include antiapoptotic activities, anti-inflammatory activities, inhibition of the inflammasome, stabilization of endothelial barrier functions including the BBB, and neurogenesis. (D) The polypeptide structure of APC comprises an N-terminal GLA domain (green) that binds to negatively charged lipids and EPCR, 2 EGF-like domains (blue), and the protease domain containing the active site triad of serine, histidine, and aspartic acid residues (red). Four glycosylation sites are indicated by gray-shaded moieties. Substrate selectivity of this protease is determined by interactions between the targeted substrates and the active site and also by multiple unique binding exosites on APC that vary for different substrates. The protease domain space–filled model (see insert) highlights in the yellow box 3 positively charged lysine (K) residues within the so-called 37 loop (KKK 191-193), which is an exosite for APC’s recognition of factors Va and VIIIa. Mutation of these 3 residues to alanine (3K3A-APC) reduces APC’s anticoagulant activity by >90%, but it does not affect its interactions with the cytoprotective substrates, PAR1, or its other known cell signaling receptors. Thus, 3K3A-APC is very signaling selective.

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