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TitleGating mechanism of the two-pore-domain potassium channel THIK1.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 7, Page 1175-1182, Year 2025
Publish dateApr 30, 2025
AuthorsXiangyun Fang / Haichao Jin / Jin Wang / Ran Zhang / Baobin Li /
PubMed AbstractTWIK-related halothane-inhibited potassium channel (THIK1) maintains the resting membrane potential and regulates potassium efflux in microglia. It is a potential therapeutic target for ...TWIK-related halothane-inhibited potassium channel (THIK1) maintains the resting membrane potential and regulates potassium efflux in microglia. It is a potential therapeutic target for neurodegenerative disorders, neuropathic pain and inflammation. However, the mechanism underlying its function remains unclear. Here we used cryo-electron microscopy to solve the structures of full-length human THIK1, revealing two inner gates and a C-type selectivity filter gate, distinct from other two-pore-domain potassium channels. One inner gate, formed by a short helix in the distal C terminus, introduces a unique gating mechanism involving the distal cytoplasmic domain. The other, beneath the selectivity filter, is constricted by Y273 in the M4 helix, dividing the cavity. In addition, the selectivity filter gate is modulated by polyunsaturated fatty acids. These structural insights into THIK1 gating, through the distal C-terminal helices, hydrophilic residues and selectivity filter, advance our understanding of THIK1's role in microglial homeostasis and neuropathologies.
External linksNat Struct Mol Biol / PubMed:40307591
MethodsEM (single particle)
Resolution2.74 - 3.07 Å
Structure data

EMDB-61467, PDB-9jgz:
Cryo-EM Structure of Human Kcnk13.
Method: EM (single particle) / Resolution: 2.74 Å

EMDB-61469, PDB-9jh1:
The Cryo-EM structure of Kcnk13-S136P
Method: EM (single particle) / Resolution: 3.07 Å

Chemicals

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

ChemComp-EIC:
LINOLEIC ACID

ChemComp-ACD:
ARACHIDONIC ACID

ChemComp-D21:
(2R)-1-(hexadecanoyloxy)-3-(phosphonooxy)propan-2-yl (9Z)-octadec-9-enoate

ChemComp-K:
Unknown entry

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / potassium channel / microglia function / K2P family / neurodegenerative diseases. / cryo-EM structure / neurodegenerative diseases

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