Phosphatidylinositol 4,5-bisphosphate activation mechanism of human KCNQ5
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 (PIP<sub>2</sub>). Here, we report cryoelectron microscopy structures of the human KCNQ5-calmodulin (CaM) complex in the apo, PIP<sub>2</sub>-bound, and both PIP<sub>2</sub>- and the activator HN37-bound states in either a closed or an open conformation. In the closed conformation, a PIP<sub>2</sub> molecule binds in the middle of the groove between two adjacent voltage-sensing domains (VSDs), whereas in the open conformation, one additional PIP<sub>2</sub> 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 PIP<sub>2</sub> and elucidate the PIP<sub>2</sub> activation mechanism of KCNQ5.
Authors
- Tiefeng Song (ORCID: https://orcid.org/0000-0001-9830-7868)
- Nannan Su (ORCID: https://orcid.org/0000-0002-8737-0412)
- Jiangtao Guo (ORCID: https://orcid.org/0000-0002-8850-286X)
- Demin Ma (ORCID: https://orcid.org/0000-0002-2730-3680)
- Fajun Nan (ORCID: https://orcid.org/0000-0002-2284-3637)
- Jiatong Zhang (ORCID: https://orcid.org/0009-0007-5160-4137)
- Zhaobing Gao (ORCID: https://orcid.org/0000-0001-8931-5508)
- Yueming Zheng (ORCID: https://orcid.org/0000-0003-0677-0316)
- Zhenni Yang (ORCID: https://orcid.org/0009-0002-1837-2788)
- Yong Wang (ORCID: https://orcid.org/0000-0001-9156-0377)
- Yan Zhang (ORCID: https://orcid.org/0000-0003-2189-0244)
- Long Wang
Institutions
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- University Medical Center (US)
- Zhejiang Cancer Hospital (CN)
- Shanghai Institute of Materia Medica (CN)
- Interface (United Kingdom) (GB)
- University of Chinese Academy of Sciences (CN)
- Zhejiang University (CN)
- Academia Sinica (TW)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-04-02
- DOI
- https://doi.org/10.1073/pnas.2416738122
- Citations
- 1
- Primary Topic
- Ion channel regulation and function
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China