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    Competing Roles of Ca2+ and Nonmuscle Myosin IIA on the Dynamics of the Metastasis-Associated Protein S100A4
    (Amer Chemical Soc, 2021) Yildirim, Ahmet; Tekpinar, Mustafa; Wassenaar, Tsjerk A.
    The calcium-binding protein S100A4 plays an important role in a wide range of biological processes such as cell motility, invasion, angiogenesis, survival, differentiation, contractility, and tumor metastasis and interacts with a range of partners. To understand the functional roles and interplay of S100A4 binding partners such as Ca2+ and nonmuscle myosin IIA (NMIIA), we used molecular dynamics simulations to investigate apo S100A4 and four holo S100A4 structures: S100A4 bound to Ca2+, S100A4 bound to NMIIA, S100A4 bound to Ca2+ and NMIIA, and a mutated S100A4 bound to Ca2+ and NMIIA. Our results show that two competing factors, namely, Ca2+-induced activation and NMIIA-induced inhibition, modulate the dynamics of S100A4 in a competitive manner. Moreover, Ca2+ binding results in enhanced dynamics, regulating the interactions of S100A4 with NMIIA, while NMIIA induces asymmetric dynamics between the chains of S100A4. The results also show that in the absence of Ca2+ the S100A4-NMIIA interaction is weak compared to that of between S100A4 bound to Ca2+ and NMIIA, which may offer a quick response to dropping calcium levels. In addition, certain mutations are shown to play a marked role on the dynamics of S100A4. The results described here contribute to understanding the interactions of S100A4 with NMIIA and the functional roles of Ca2+, NMIIA, and certain mutations on the dynamics of S100A4. The results of this study could be interesting for the development of inhibitors that exploit the shift of balance between the competing roles of Ca2+ and NMIIA.
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    Öğe
    Molecular dynamics study of the effect of active site protonation on Helicobacter pylori 5?-methylthioadenosine/S-adenosylhomocysteine nucleosidase
    (Springer Verlag, 2015) Tekpinar, Mustafa; Yildirim, Ahmet; Wassenaar, Tsjerk A.
    The protein 5?-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is involved in the quorum sensing of several bacterial species, including Helicobacter pylori. In particular, these bacteria depend on MTAN for synthesis of vitamin K2 homologs. The residue D198 in the active site of MTAN seems to be of crucial importance, by acting as a hydrogen-bond acceptor for the ligand. In this study, we investigated the conformation and dynamics of apo and holo H. pylori MTAN (HpMTAN), and assessed the effect of protonation of D198 by use of molecular dynamics simulations. Our results show that protonation of the active site of HpMTAN can cause a conformational transition from a closed state to an open state even in the absence of substrate, via inter-chain mechanical coupling. © 2015, European Biophysical Societies' Association.