| text | During the initiation phase of coagulation, factor IX (FIX) interacts with tissue factor (TF)-bound factor VIIa (FVIIa) forming the ternary TF:FVIIa:FIX complex where FIX is converted to FIXa (Osterud B & Rapaport SI 1977; Komiyama Y et al., 1990; Kirchhofer D et al., 2000; Zhong D et al. 2002). The conversion of FIX to FIXa requires proteolytic cleavages after Arg191 and Arg226. Upon this cleavage, the activation peptide (Ala192-Arg226) is released leaving the light chain, FIX (47-191), and the heavy chain, FIX (227-461), that are held together by a disulfide bond to form the activated factor IX (FIXa) (Di Scipio RG et al., 1978; Yoshitake S et al. 1985; Geng Y et al., 2012; reviewed by Vadivel K & Bajaj SP 2012). This cleavage is catalyzed by the protease activity of FVIIa in the presence of TF and phosphatidylserine-rich phospholipid in the Ca2+-dependent manner (Osterud B & Rapaport SI 1977; Komiyama Y et al., 1990; Banner DW et al. 1996; Lu G et al., 2004; Bajaj SP et al. 2006). The light chain of FIX contains the gamma-carboxyglutamic acid (Gla) domain, and two epidermal growth factor-like (EGF1 and EGF2) domains. The heavy FIX (227-461) chain contains the catalytic protease domain (Yoshitake S et al. 1985). Gla and EGF1 domains of FIX are responsible for the interaction with FVIIa and TF, facilitating the formation of the ternary complex (Zhong D et al. 2002; Thiec F et al., 2003; Ndonwi M et al., 2005; reviewed by Vadivel K & Bajaj SP 2012). Additionally, FIX binds to phospholipid membranes through the Gla domain (Jacobs M et al. 1994; Huang M et al., 2004). Further, computational models of TF:FVIIa:FIX or TF:FVIIa:FX suggest that in the formed ternary complex, the scissile peptide bond in FIX (and in the structurally similar FX) moves toward the active site cleft in FVIIa, triggering the formation of the oxyanion hole in FVIIa to enable efficient proteolysis (Vadivel K & Bajaj SP 2012). FVIIa, bound to TF at the endothelial cell surface, cleaves FIX first after Arg191, forming the inactive intermediate which is released from FVIIa. The intermediate form of FIX must rebind to the protease to be cleaved after Arg226 to form an activated FIXa. As the second cleavage is rate-limiting, the inactive intermediate accumulates during FIX activation by FVIIa (reviewed by Vadivel K & Bajaj SP 2012). |
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