Phosphatidylinositol 4,5-bisphosphate activation mechanism of human KCNQ5

• 成果类型: Article
• 署名作者: Yang, Zhenni; Zheng, Yueming; Ma, Demin; Wang, Long; Zhang, Jiatong; Song, Tiefeng; Wang, Yong; Zhang, Yan; Nan, Fajun; Su, Nannan; Gao, Zhaobing; Guo, Jiangtao
• 署名单位: Zhejiang University; Zhejiang University; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Zhejiang University; Zhejiang University; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Liangzhu Laboratory; Zhejiang University; Zhejiang University; Chinese Academy of Medical Sciences - Peking Union Medical College; Zhejiang University; Zhejiang University; Zhejiang University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13365
• DOI: 10.1073/pnas.2416738122
• 发表日期: 2025-04-08
• 关键词: potassium channel gene; voltage-sensor; inositol trisphosphate; pip2; modulation; membrane; anticonvulsant; excitability; cytoskeleton; contribute

摘要

The human voltage-gated potassium channels KCNQ2, KCNQ3, and KCNQ5 can form homo-and heterotetrameric channels that are responsible for generating the neuronal M current and maintaining the membrane potential stable. Activation of KCNQ channels requires both the depolarization of membrane potential and phosphatidylinositol 4,5-bisphosphate (PIP2). Here, we report cryoelectron microscopy structures of the human KCNQ5-calmodulin (CaM) complex in the apo, PIP2-bound, and both PIP2-and the activator HN37-bound states in either a closed or an open conformation. In the closed conformation, a PIP2 molecule binds in the middle of the groove between two adjacent voltage-sensing domains (VSDs), whereas in the open conformation, one additional PIP2 binds to the interface of VSD and the pore domain, accompanying structural rearrangement of the cytosolic domain of KCNQ and CaM. The structures, along with electrophysiology analyses, reveal the two different binding modes of PIP2 and elucidate the PIP2 activation mechanism of KCNQ5.