Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
Dipartimento di Ingegneria Meccanica e Aerospaziale, Sapienza Università di Roma, Rome, Italy.
Nat Commun. 2023 Feb 27;14(1):1110. doi: 10.1038/s41467-023-36730-7.
Voltage-gated potassium channels are involved in many physiological processes such as nerve impulse transmission, the heartbeat, and muscle contraction. However, for many of them the molecular determinants of the gating mechanism remain elusive. Here, using a combination of theoretical and experimental approaches, we address this problem focusing on the cardiac hERG potassium channel. Network analysis of molecular dynamics trajectories reveals the presence of a kinematic chain of residues that couples the voltage sensor domain to the pore domain and involves the S4/S1 and S1/S5 subunit interfaces. Mutagenesis experiments confirm the role of these residues and interfaces in the activation and inactivation mechanisms. Our findings demonstrate the presence of an electromechanical transduction path crucial for the non-domain-swapped hERG channel gating that resembles the noncanonical path identified in domain-swapped K channels.
电压门控钾通道参与许多生理过程，如神经冲动传递、心跳和肌肉收缩。然而，对于它们中的许多通道，门控机制的分子决定因素仍然难以捉摸。在这里，我们使用理论和实验相结合的方法，专注于心脏 hERG 钾通道来解决这个问题。分子动力学轨迹的网络分析揭示了存在一个运动链残基，它将电压传感器结构域与孔结构域连接起来，并涉及 S4/S1 和 S1/S5 亚基界面。突变实验证实了这些残基和界面在激活和失活机制中的作用。我们的研究结果表明，存在一种机电转导途径，对于非结构域交换的 hERG 通道门控至关重要，类似于在结构域交换的 K 通道中发现的非典型途径。
