Competing Roles of Ca2+ and Nonmuscle Myosin IIA on the Dynamics of the Metastasis-Associated Protein S100A4,The Journal of Physical Chemistry B

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Competing Roles of Ca2+ and Nonmuscle Myosin IIA on the Dynamics of the Metastasis-Associated Protein S100A4
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2021-08-31 , DOI: 10.1021/acs.jpcb.1c02096
Ahmet Yildirim ₁ , Mustafa Tekpinar ₂ , Tsjerk A Wassenaar _{3,

4}

Affiliation

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.

中文翻译：

Ca2+ 和非肌肉肌球蛋白 IIA 在转移相关蛋白 S100A4 动力学中的竞争作用

钙结合蛋白 S100A4 在细胞运动、侵袭、血管生成、存活、分化、收缩和肿瘤转移等广泛的生物过程中发挥重要作用，并与一系列伙伴相互作用。为了了解 S100A4 结合伙伴如 Ca ²⁺和非肌肉肌球蛋白 IIA (NMIIA) 的功能作用和相互作用，我们使用分子动力学模拟来研究 apo S100A4 和四个全息 S100A4 结构：S100A4 与 Ca ²⁺结合，S100A4 与 NMIIA 结合，S100A4 与 Ca ²⁺和 NMIIA 结合，突变的 S100A4 与 Ca ²⁺和 NMIIA 结合。我们的结果表明，两个相互竞争的因素，即 Ca ²⁺- 诱导的激活和 NMIIA 诱导的抑制，以竞争方式调节 S100A4 的动力学。此外，Ca ²⁺结合导致增强的动力学，调节 S100A4 与 NMIIA 的相互作用，而 NMIIA 诱导 S100A4 链之间的不对称动力学。结果还表明，在没有 Ca ²⁺的情况下，S100A4-NMIIA 的相互作用比与 Ca 2+ 结合的 S100A4 和 NMIIA 之间的相互作用弱^，这可能对钙水平的下降提供快速响应。此外，某些突变被证明对 S100A4 的动力学具有显着作用。这里描述的结果有助于理解 S100A4 与 NMIIA 的相互作用以及 Ca ^{2+的功能作用}、NMIIA 和 S100A4 动力学的某些突变。这项研究的结果对于开发利用 Ca ²⁺和 NMIIA 竞争作用之间平衡转变的抑制剂可能很有趣。

更新日期：2021-09-16

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