Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, Washington, USA.
Department of Plant Pathology, Washington State University, Pullman, Washington, USA.
Protein Sci. 2021 Feb;30(2):423-437. doi: 10.1002/pro.4000. Epub 2020 Dec 2.
Tropomodulins are a family of important regulators of actin dynamics at the pointed ends of actin filaments. Four isoforms of tropomodulin, Tmod1-Tmod4, are expressed in vertebrates. Binding of tropomodulin to the pointed end is dependent on tropomyosin, an actin binding protein that itself is represented in mammals by up to 40 isoforms. The understanding of the regulatory role of the tropomodulin/tropomyosin molecular diversity has been limited due to the lack of a three-dimensional structure of the tropomodulin/tropomyosin complex. In this study, we mapped tropomyosin residues interacting with two tropomyosin-binding sites of tropomodulin and generated a three-dimensional model of the tropomodulin/tropomyosin complex for each of these sites. The models were refined by molecular dynamics simulations and validated via building a self-consistent three-dimensional model of tropomodulin assembly at the pointed end. The model of the pointed-end Tmod assembly offers new insights in how Tmod binding ensures tight control over the pointed end dynamics.
原肌球蛋白是肌动蛋白丝尖端肌动蛋白动态的重要调节因子家族。原肌球蛋白在脊椎动物中表达 4 种同工型，Tmod1-Tmod4。原肌球蛋白与尖端的结合依赖于原肌球蛋白，原肌球蛋白本身在哺乳动物中由多达 40 种同工型组成。由于缺乏原肌球蛋白/肌动蛋白的三维结构，因此对原肌球蛋白/肌动蛋白分子多样性的调节作用的理解受到限制。在这项研究中，我们绘制了与原肌球蛋白结合的原肌球蛋白残基，与原肌球蛋白的两个肌动蛋白结合位点，并为这两个位点的每一个生成了原肌球蛋白/原肌球蛋白复合物的三维模型。通过分子动力学模拟对模型进行了优化，并通过构建原肌球蛋白在尖端的自洽三维组装模型进行了验证。该模型提供了关于 Tmod 结合如何确保对尖端动力学的严格控制的新见解。
