Structural Insights into Zn2+ and Ca2+ binding to Human Protein Z and Their Impact on Membrane Association
Gayathri, C. S.; Gupta, S.; SENGUPTA, T.; Sarkar, S.
Show abstract
Calcium ions (Ca{superscript 2}) bound to the {gamma}-carboxy glutamic acid-rich (Gla) domain of coagulation proteins are essential for their membrane anchoring. Zinc ions (Zn{superscript 2}), abundant in plasma, also bind coagulation proteins and modulate their activity. However, their role in membrane-protein interactions remains less understood. The current study examines how Ca{superscript 2} and Zn{superscript 2} influence the structure and function of human protein Z (PZ), a cofactor of protein Z-dependent protease inhibitor (ZPI) that inhibits factor Xa on phospholipid surfaces. Zn2+ was found to substitute for Ca2+ in the Gla domain of PZ and promote its membrane binding by inducing conformational changes like Ca2+. Additionally, a Zn2+ located in the epidermal growth factor1 (EGF1) domain of PZ appeared to synergize with Ca2+ to enhance the membrane affinity of PZ. Furthermore, both Ca2+ and Zn2+ were suggested to destabilize PZ-ZPI complex, thereby modulating the cofactor activity of PZ, a finding that warrants further experimental investigations. Collectively, this study provides the first structural and functional characterization of Zn{superscript 2}-bound PZ, offering new insights into metal ion driven structural dynamics of PZ and their implications in coagulation regulation.
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