Abstract Number: PB0561
Meeting: ISTH 2022 Congress
Background: Calcium ion plays a pivotal role in blood coagulation. Primarily, it helps in proper folding of the Gla domain through which coagulation proteins bind to the membrane surface. Zinc, the second most abundant cation in plasma and another key regulator of coagulation, has also been shown to bind in the Gla domains of a few coagulation proteins (fVIIa, PC, fXII). However, whether it can exert similar structural effect like Ca2+ is not clear.
Aims: The current study is therefore aimed to find if Zn2+ induces any conformational change in the Gla domain of the anticoagulant PZ, and help in its membrane binding. A comparison on the the effects of Zn2+ and Ca2+ binding on the structure of PZ revealed structural changes that may have potential implications on the dynamics of the PZ-ZPI complex and membrane binding
Methods: Full length apo-PZ structure was modelled using homology modeling and geometry minimization. Ca2+ and Zn2+ bound holo structures of PZ and PZ-ZPI complex were then subjected to MD simulation using AMBER.
Results: Ca2+ induces a conformational change in apo-PZ where the Gla domain moves towards SP like domain. The folded Gla domain of the holo-protein appears to create a pocket that may stabilize the PZ-ZPI interaction. Replacing Ca2+ ions by Zn2+ in the holo structure showed no appreciable change in the overall conformation of PZ (Figure 1). However, de novo Zn2+ binding cannot cause the apo protein to fold as much as it does in presence of Ca2+. One Zn2+ was also found to be present in the EGF domain of PZ, inducing important structural changes that may influence membrane binding.
Conclusion(s): Zn2+ induces similar structural changes in the Gla domain of PZ as exerted by Ca2+ and therefore can regulate the activity of PZ-ZPI system by augmenting the lipid binding of PZ.
To cite this abstract in AMA style:Sengupta T, Gayathri S, Gupta S. Ca2+ and Zn2+ binding to human Protein Z (PZ) induces structural changes that augments its lipid binding [abstract]. https://abstracts.isth.org/abstract/ca2-and-zn2-binding-to-human-protein-z-pz-induces-structural-changes-that-augments-its-lipid-binding/. Accessed September 22, 2023.
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