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<p>The polycystin complex, consisting of one&#xa0;polycystin-1 (PC1) and three&#xa0;polycystin-2 (PC2), forms a cation channel localized to the primary cilium and is critically involved in autosomal dominant polycystic kidney disease (ADPKD). This study reveals an allosteric gating mechanism of the PC1-PC2 channel modulated by specific membrane lipids. In typical membrane environments, phosphatidylglycerol (PG) and phosphatidic acid (PA) bind to the channel central pore, maintaining it in a closed state. Dissociation of these lipids transitions the channel to a pre-open state. The cilia-enriched oxysterol 7β,27-dihydroxycholesterol (7β,27-DHC) stabilizes the channel in a more open but still non-conductive conformation through an allosteric mechanism. Lipid-mediated regulation is coupled to large conformational rearrangements of the TOP and voltage-sensor-like domains&#xa0;(VSDs) of the third PC2 subunit, which eventually leads to pore opening. This lipid-dependent modulation is also observed in a gain-of-function channel. These findings reveal a distinct gating mechanism for the asymmetric 1:3 PC1-PC2 complex.</p>

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Structural basis of lipid-dependent allosteric gating mechanisms for PC1-PC2 ion channel

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Mengying Chen,
  • Zhifei Wang,
  • Yan Shi,
  • Gaoxingyu Huang,
  • Tiago D. C. Morais,
  • Akhilraj R. Pillai,
  • Yan Wang,
  • Moushumi Afroza Mou,
  • Dan Jing,
  • Rongyan Fan,
  • Fayang Zhou,
  • Zhangsuo Liu,
  • Qiang Su,
  • Yong Yu,
  • Yigong Shi

摘要

The polycystin complex, consisting of one polycystin-1 (PC1) and three polycystin-2 (PC2), forms a cation channel localized to the primary cilium and is critically involved in autosomal dominant polycystic kidney disease (ADPKD). This study reveals an allosteric gating mechanism of the PC1-PC2 channel modulated by specific membrane lipids. In typical membrane environments, phosphatidylglycerol (PG) and phosphatidic acid (PA) bind to the channel central pore, maintaining it in a closed state. Dissociation of these lipids transitions the channel to a pre-open state. The cilia-enriched oxysterol 7β,27-dihydroxycholesterol (7β,27-DHC) stabilizes the channel in a more open but still non-conductive conformation through an allosteric mechanism. Lipid-mediated regulation is coupled to large conformational rearrangements of the TOP and voltage-sensor-like domains (VSDs) of the third PC2 subunit, which eventually leads to pore opening. This lipid-dependent modulation is also observed in a gain-of-function channel. These findings reveal a distinct gating mechanism for the asymmetric 1:3 PC1-PC2 complex.