Modeling and dynamics of the full-length structure of the factor XII protein: Insights into the mechanism of activation through zinc binding

Kılınç E., Öztuğ M., Timuçin E.

30th ANNUAL BIOPHYSICS CONGRESS (INTERNATIONAL), Muğla, Turkey, 10 - 13 October 2018, pp.1-63

  • Publication Type: Conference Paper / Summary Text
  • City: Muğla
  • Country: Turkey
  • Page Numbers: pp.1-63
  • Acibadem Mehmet Ali Aydinlar University Affiliated: Yes


Introduction: Zinc, the second most abundant transition metal in blood, plays a crucial role in coagulation as zinc deficiency has been associated with bleeding disorders. Essentially, zinc has been shown to bind to the initiator of the contact pathway, factor (F) XII. Zinc binding induces conformational changes in the structure of F XII, which augments its activation. F XII consists of two chains, the heavy and light chain. The structure of the light chain has been determined by X-ray crystallography, albeit accurate biophysical characterization of the full-length structure remains to be a challenge due to the presence of intrinsically disordered regions in the heavy chain. Prompted by mutagenesis studies that identified 4 zinc binding sites in the heavy chain of F XII, we underscore the necessity of acquiring the full-length structure of F XII in order to comprehend the structural role of zinc in the activation of F XII. Methods: To this end, we recruited comparative modeling tools to obtain the the fulllength structure of human Factor XII, and molecular dynamics simulations to refine the structural model. Results: Modeling and dynamical analysis of the full-length structure strikingly indicated potential zinc coordination sites compliant with the experiments. Conclusions: Overall, this study proposes a molecular mechanism for the zincinduced activation of Factor XII, highlighting the potential use of computational approaches for addressing biophysical questions. Key words: Factor XII, Zinc, Blood Coagulation, Molecular Dynamics, Comparative Modeling