Scholarlink

<p>Polyunsaturated fatty acid (PUFA) lipids modulate the neuronal and microglial leak potassium channel K<sub>2P</sub>13.1 (THIK1) and other voltage-gated ion channel (VGIC) superfamily members through poorly understood mechanisms. Here we present cryo-electron microscopy structures of human THIK1 and mutants, revealing a unique two-chamber aqueous inner cavity obstructed by a hydrophilic barrier important for gating, the flow restrictor, and a P1–M4 intersubunit interface lipid at a site, the PUFA site, corresponding to the K<sub>2P</sub> small-molecule modulator pocket. This overlap, together with functional studies, indicates that PUFA site lipids are THIK1 cofactors. Comparison with a PUFA-responsive VGIC, K<sub>v</sub>7.1, reveals a shared modulatory role for the pore domain intersubunit interface, providing a framework for understanding PUFA action on the VGIC superfamily. Our findings reveal the distinct THIK1 architecture, highlight the importance of the P1–M4 interface for K<sub>2P</sub> control by natural and synthetic ligands and should aid in the development of THIK subfamily modulators for neuroinflammation and autism.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Structure of the human K2P13.1 channel reveals a hydrophilic pore restriction and lipid cofactor site

  • 期刊论文

  • 发表日期：

    2025年2月26日

查看全文
  • Shatabdi Roy-Chowdhury,
  • Seil Jang,
  • Fayal Abderemane-Ali,
  • Fiona Naughton,
  • Michael Grabe,
  • Daniel L. Minor Jr.

摘要

Polyunsaturated fatty acid (PUFA) lipids modulate the neuronal and microglial leak potassium channel K2P13.1 (THIK1) and other voltage-gated ion channel (VGIC) superfamily members through poorly understood mechanisms. Here we present cryo-electron microscopy structures of human THIK1 and mutants, revealing a unique two-chamber aqueous inner cavity obstructed by a hydrophilic barrier important for gating, the flow restrictor, and a P1–M4 intersubunit interface lipid at a site, the PUFA site, corresponding to the K2P small-molecule modulator pocket. This overlap, together with functional studies, indicates that PUFA site lipids are THIK1 cofactors. Comparison with a PUFA-responsive VGIC, Kv7.1, reveals a shared modulatory role for the pore domain intersubunit interface, providing a framework for understanding PUFA action on the VGIC superfamily. Our findings reveal the distinct THIK1 architecture, highlight the importance of the P1–M4 interface for K2P control by natural and synthetic ligands and should aid in the development of THIK subfamily modulators for neuroinflammation and autism.