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Structure paper

TitlePhosphatidylinositol 4,5-bisphosphate activation mechanism of human KCNQ5.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 14, Page e2416738122, Year 2025
Publish dateApr 8, 2025
AuthorsZhenni Yang / Yueming Zheng / Demin Ma / Long Wang / Jiatong Zhang / Tiefeng Song / Yong Wang / Yan Zhang / Fajun Nan / Nannan Su / Zhaobing Gao / Jiangtao Guo /
PubMed AbstractThe 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 ...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). Here, we report cryoelectron microscopy structures of the human KCNQ5-calmodulin (CaM) complex in the apo, PIP-bound, and both PIP- and the activator HN37-bound states in either a closed or an open conformation. In the closed conformation, a PIP molecule binds in the middle of the groove between two adjacent voltage-sensing domains (VSDs), whereas in the open conformation, one additional PIP 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 and elucidate the PIP activation mechanism of KCNQ5.
External linksProc Natl Acad Sci U S A / PubMed:40172963 / PubMed Central
MethodsEM (single particle)
Resolution2.4 - 3.2 Å
Structure data

EMDB-61109, PDB-9j38:
human KCNQ5-CaM in apo state
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-63128, PDB-9liz:
Human KCNQ5-CaM in complex with PIP2
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-63130, PDB-9lj1:
Human KCNQ5-CaM-PIP2-HN37 complex in a closed conformation.
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-63133, PDB-9lj5:
Human KCNQ5-CaM-PIP2-HN37 complex in an open conformation.
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

ChemComp-9MF:
methyl N-[4-[(4-fluorophenyl)methyl-prop-2-ynyl-amino]-2,6-dimethyl-phenyl]carbamate

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / voltage-gated potassium channel

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