Zhu Cheng, Zhou Xuejie, Liu Ziteng, Chen Hongwei, Wu Hongfeng, Yang Xiao, Zhu Xiangdong, Ma Jing, Dong Hao
Kuang Yaming Honors School, Nanjing University, Nanjing, China.
Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin, China.
Front Mol Biosci. 2021 Mar 4;8:627015. doi: 10.3389/fmolb.2021.627015. eCollection 2021.
The clathrin-associated protein adaptin-2 (AP2) is a distinctive member of the hetero-tetrameric clathrin adaptor complex family. It plays a crucial role in many intracellular vesicle transport pathways. The hydroxyapatite (HAp) nanoparticles can enter cells through clathrin-dependent endocytosis, induce apoptosis, and ultimately inhibit tumor metastasis. Exploring the micro process of the binding of AP2 and HAp is of great significance for understanding the molecular mechanism of HAp's anti-cancer ability. In this work, we used molecular modeling to study the binding of spherical, rod-shaped, and needle-shaped HAps toward AP2 protein at the atomic level and found that different nanoparticles' morphology can determine their binding specificity through electrostatic interactions. Our results show that globular HAp significantly changes AP2 protein conformation, while needle-shaped HAP has more substantial binding energy with AP2. Therefore, this work offers a microscopic picture for cargo recognition in clathrin-mediated endocytosis, clarifies the design principles and possible mechanisms of high-efficiency nano-biomaterials, and provides a basis for their potential anti-tumor therapeutic effects.
网格蛋白相关蛋白衔接蛋白-2（AP2）是异源四聚体网格蛋白衔接复合物家族的一个独特成员。它在许多细胞内囊泡运输途径中起着关键作用。羟基磷灰石（HAp）纳米颗粒可通过网格蛋白介导的内吞作用进入细胞，诱导细胞凋亡，并最终抑制肿瘤转移。探索AP2与HAp结合的微观过程对于理解HAp抗癌能力的分子机制具有重要意义。在这项工作中，我们使用分子建模在原子水平上研究了球形、棒状和针状HAp与AP2蛋白的结合，发现不同纳米颗粒的形态可以通过静电相互作用决定它们的结合特异性。我们的结果表明，球状HAp显著改变AP2蛋白构象，而针状HAp与AP2具有更强的结合能。因此，这项工作为网格蛋白介导的内吞作用中的货物识别提供了微观图景，阐明了高效纳米生物材料的设计原则和可能机制，并为其潜在的抗肿瘤治疗效果提供了依据。
