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Evolutionary Adaptations in Pseudonaja Textilis Venom Factor X Induce Zymogen Activity and Resistance to the Intrinsic Tenase Complex
activators consisting of factor X (v-ptFX)- and factor V-like proteins. While all vertebrate
liver-expressed factor X (FX) homologs, including that of P. textilis, comprise an
activation peptide of approximately 45 to 65 residues, the activation peptide of vptFX
is significantly shortened to 27 residues. In this study, we demonstrate that
exchanging the human FX activation peptide for the snake venom ortholog impedes
proteolytic cleavage by the intrinsic factor VIIIa–factor IXa tenase complex. Furthermore,
our findings indicate that the human FX activation peptide comprises an
essential binding site for the intrinsic tenase complex. Conversely, incorporation of
FX into the extrinsic tissue factor–factor VIIa tenase complex is completely dependent
on exosite-mediated interactions. Remarkably, the shortened activation peptide allows
for factor...Show moreThe venom of the Australian snake Pseudonaja textilis comprises powerful prothrombin
activators consisting of factor X (v-ptFX)- and factor V-like proteins. While all vertebrate
liver-expressed factor X (FX) homologs, including that of P. textilis, comprise an
activation peptide of approximately 45 to 65 residues, the activation peptide of vptFX
is significantly shortened to 27 residues. In this study, we demonstrate that
exchanging the human FX activation peptide for the snake venom ortholog impedes
proteolytic cleavage by the intrinsic factor VIIIa–factor IXa tenase complex. Furthermore,
our findings indicate that the human FX activation peptide comprises an
essential binding site for the intrinsic tenase complex. Conversely, incorporation of
FX into the extrinsic tissue factor–factor VIIa tenase complex is completely dependent
on exosite-mediated interactions. Remarkably, the shortened activation peptide allows
for factor V-dependent prothrombin conversion while in the zymogen state. This
indicates that the active site of FX molecules comprising the v-ptFX activation peptide
partially matures upon assembly into a premature prothrombinase complex. Taken
together, the shortened activation peptide is one of the remarkable characteristics of vptFX
that has been modified from its original form, thereby transforming FX into a
powerful procoagulant protein. Moreover, these results shed new light on the
structural requirements for serine protease activation and indicate that catalytic
activity can be obtained without formation of the characteristic Ile16–Asp194 salt
bridge via modification of the activation peptide.Show less
- All authors
- Schreuder, M.; Poenou, G.P.; Strijbis, V.J.F.; Cheung, K.L.; Reitsma, P.H.; Bos, M.H.A.
- Date
- 2020
- Journal
- Thrombosis and Haemostasis