LT Materials, Gyeonggi-Do 11319, Republic of Korea.
Department of Applied Chemistry, University of Seoul, Seoul 02504, Republic of Korea.
J Chem Phys. 2023 Jul 7;159(1). doi: 10.1063/5.0153799.
Cytokinesis requires a apoptosis-linked gene 2 interacting protein X (ALIX) and a 55 kDa midbody centrosomal protein (CEP55) to activate the cell abscission in somatic cells. However, in germ cells, CEP55 forms intercellular bridges with testis-expressed gene 14 (TEX14), which blocks the cell abscission. These intercellular bridges play important roles in the synchronization of the germ cells and facilitate the coordinated passage of organelles and molecules between germ cells. If TEX14 is intentionally removed, intercellular bridges are disrupted, leading to sterility. Hence, a deeper understanding regarding the roles of TEX14 can provide significant insights into the inactivation of abscission and the inhibition of proliferation in cancer cells. Previous experimental studies have shown that the high affinity and low dissociation rate of TEX14 for CEP55 prevent ALIX from binding CEP55 and inactivate the germ cell abscission. However, detailed information about how TEX14 interacts with CEP55 to prevent the cell abscission is still lacking. To gain more specific insights into the interactions between CEP55 and TEX14 and the difference in reactivity between TEX14 and ALIX, we performed well-tempered metadynamics simulations of these protein complexes using atomistic models of CEP55, TEX14, and ALIX. We identified the major binding residues of TEX14 and ALIX with CEP55 by using 2D Gibbs free energy evaluations, the results of which are consistent with previous experimental studies. Our results may help design synthetic TEX14 mimicking peptides, which can bind CEP55 and facilitate the inactivation of abscission in abnormal cells, including cancer cells.
有丝分裂后末期需要凋亡连接基因 2 相互作用蛋白 X（ALIX）和一个 55kDa 中心体微管蛋白（CEP55）来激活体细胞的细胞分离。然而，在生殖细胞中，CEP55 与睾丸表达基因 14（TEX14）形成细胞间桥，从而阻止细胞分离。这些细胞间桥在生殖细胞的同步化中起着重要作用，并促进细胞器和分子在生殖细胞之间的协调传递。如果故意去除 TEX14，细胞间桥就会被破坏，导致不育。因此，深入了解 TEX14 的作用可以为深入了解有丝分裂后末期的失活和癌细胞增殖的抑制提供重要的见解。先前的实验研究表明，TEX14 与 CEP55 具有高亲和力和低解离率，阻止 ALIX 与 CEP55 结合并使生殖细胞分离失活。然而，关于 TEX14 如何与 CEP55 相互作用以防止细胞分离的详细信息仍然缺乏。为了更深入地了解 CEP55 和 TEX14 之间的相互作用以及 TEX14 和 ALIX 之间反应性的差异，我们使用 CEP55、TEX14 和 ALIX 的原子模型对这些蛋白质复合物进行了经过良好调整的元动力学模拟。我们通过 2D 吉布斯自由能评估确定了 TEX14 和 ALIX 与 CEP55 的主要结合残基，结果与先前的实验研究一致。我们的结果可能有助于设计合成的 TEX14 模拟肽，这些肽可以与 CEP55 结合，并促进异常细胞（包括癌细胞）中分离的失活。
