Faculty of Biology, MSU-BIT Shenzhen University, Shenzhen 518172, China.
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow 117997, Russia.
Toxins (Basel). 2023 Oct 13;15(10):612. doi: 10.3390/toxins15100612.
Cancer progression is characterized by microenvironmental acidification. Tumor cells adapt to low environmental pH by activating acid-sensing trimeric ion channels of the DEG/ENaC family. The α-ENaC/ASIC1a/γ-ENaC heterotrimeric channel is a tumor-specific acid-sensing channel, and its targeting can be considered a new strategy for cancer therapy. Mambalgin-2 from the venom inhibits the α-ENaC/ASIC1a/γ-ENaC heterotrimer more effectively than the homotrimeric ASIC1a channel, initially proposed as the target of mambalgin-2. Although the molecular basis of such mambalgin selectivity remained unclear. Here, we built the models of the complexes of mambalgin-2 with the α-ENaC/ASIC1a/γ-ENaC and ASIC1a channels, performed MD and predicted the difference in the binding modes. The importance of the 'head' loop region of mambalgin-2 for the interaction with the hetero-, but not with the homotrimeric channel was confirmed by site-directed mutagenesis and electrophysiology. A new mode of allosteric regulation of the ENaC channels by linking the thumb domain of the ASIC1a subunit with the palm domain of the γ-ENaC subunit was proposed. The data obtained provide new insights into the regulation of various types of acid-sensing ion channels and the development of new strategies for cancer treatment.
癌症的进展以微环境酸化为特征。肿瘤细胞通过激活 DEG/ENaC 家族的酸感应三聚体离子通道来适应低环境 pH 值。α-ENaC/ASIC1a/γ-ENaC 三聚体通道是一种肿瘤特异性酸感应通道，其靶向可以被认为是癌症治疗的新策略。来自毒液的 Mambalgin-2 比同源三聚体 ASIC1a 通道更有效地抑制 α-ENaC/ASIC1a/γ-ENaC 三聚体，最初被提议为 Mambalgin-2 的靶标。尽管这种 Mambalgin 选择性的分子基础仍不清楚。在这里，我们构建了 Mambalgin-2 与 α-ENaC/ASIC1a/γ-ENaC 和 ASIC1a 通道复合物的模型，进行了 MD 模拟并预测了结合模式的差异。通过定点突变和电生理学证实了 Mambalgin-2 的“头部”环区对于与异三聚体而不是同三聚体通道相互作用的重要性。提出了一种通过将 ASIC1a 亚基的拇指结构域与 γ-ENaC 亚基的手掌结构域连接来对 ENaC 通道进行变构调节的新模式。所获得的数据为各种类型的酸感应离子通道的调节以及癌症治疗新策略的发展提供了新的见解。
