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On the early events of the calcium induced activation of coagulation factor XIII-A 2 and tissue transglutaminase - an in silico study



On the early events of the calcium induced activation of coagulation factor XIII-A 2 and tissue transglutaminase - an in silico study



Journal of Biomolecular Structure and Dynamics 2019: 1-27



Both coagulation factor XIII-A2 (FXIII-A2) and tissue transglutaminase (TG2) play distinctive and important roles in homeostasis by crosslinking proteins or peptides via isopeptide bonds. In this present study, a series of microsecond long all-atom molecular dynamics (MD) simulations were carried out in order to reveal the dynamic, atomic-level events which may contribute to the activation of these proteins via the binding of calcium ions. In addition to previously conducted in vitro and crystallographic studies, further suggestions have been made concerning the calcium binding features of these enzymes. The different systems used for running the simulations were based on the zymogen, computationally cleaved and even the activation peptide (AP-FXIII) free FXIII-A2' homodimer form. The effects of various ionic environments have also been explored in the simulations of FXIII-A2. Our results suggest that the presence of calcium ions can cause increased AP fluctuations, which ultimately could lead to their relocation on the homodimer surface. The release of these APs seem to be crucial for rotation of the A subunits based on equilibrium MD simulations. The primary evidence for this assumption comes from the predicted principal component eigenvector what is considered as the first, large scale event of the overall activation process. To get a more accurate atomic-level description, the calcium binding sites of TG2 have also been investigated in our extensive in silico experiments, which suggests the presence of a previously unidentified binding sites as well.

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Accession: 066448788

Download citation: RISBibTeXText

PMID: 30707083

DOI: 10.1080/07391102.2019.1574604


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