华东理工大学谭蔚泓研究团队报道了用DNA纳米器件实现特定蛋白质的结构域靶向膜分配。相关研究成果发表在2024年3月11日出版的《美国化学会杂志》。

细胞膜具有脂质和蛋白质的显著复杂性，它们动态地分离成不同的结构域以协调各种细胞功能。在不涉及基因修饰的情况下操纵特定膜蛋白的分配的能力，对于解码各种细胞过程是至关重要的，但极具挑战性。

该文中，通过在DNA四面体的三个底部顶点偶联胆固醇或生育酚，研究人员开发了两套纳米器件，用于选择性靶向活细胞膜上的脂质有序（Lo）和脂质无序（Ld）结构域。通过结合蛋白质识别配体，如适体或抗体，通过脚位介导的链置换，这些DNA纳米器件能够使靶蛋白在这两个结构域之间动态易位。

研究人员首先使用PTK7作为蛋白质模型，并首次证明PTK7向Lo结构域的积累可以促进肿瘤细胞的迁移，而将其螯合在Ld结构域中会抑制细胞的运动。接下来，基于其模块化性质，这些DNA纳米器件被扩展为通过操纵CD45在Lo和Ld结构域之间的易位来调节T细胞活化过程。

因此，该工作有望为研究不同细胞信号传导过程中的膜结构和分子相互作用提供深入的见解。

附：英文原文

Title: Domain-Targeted Membrane Partitioning of Specific Proteins with DNA Nanodevices

Author: Yong-Hao Ma, Yan Zhu, Hui Wu, Yao He, Qiang Zhang, Qiuling Huang, Zhimin Wang, Hang Xing, Liping Qiu, Weihong Tan

Issue&Volume: March 11, 2024

Abstract: The cell membrane exhibits a remarkable complexity of lipids and proteins that dynamically segregate into distinct domains to coordinate various cellular functions. The ability to manipulate the partitioning of specific membrane proteins without involving genetic modification is essential for decoding various cellular processes but highly challenging. In this work, by conjugating cholesterols or tocopherols at the three bottom vertices of the DNA tetrahedron, we develop two sets of nanodevices for the selective targeting of lipid-order (Lo) and lipid-disorder (Ld) domains on the live cell membrane. By incorporation of protein-recognition ligands, such as aptamers or antibodies, through toehold-mediated strand displacement, these DNA nanodevices enable dynamic translocation of target proteins between these two domains. We first used PTK7 as a protein model and demonstrated, for the first time, that the accumulation of PTK7 to the Lo domains could promote tumor cell migration, while sequestering it in the Ld domains would inhibit the movement of the cells. Next, based on their modular nature, these DNA nanodevices were extended to regulate the process of T cell activation through manipulating the translocation of CD45 between the Lo and the Ld domains. Thus, our work is expected to provide deep insight into the study of membrane structure and molecular interactions within diverse cell signaling processes.

DOI: 10.1021/jacs.3c13966

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.3c13966