Structural mechanisms of phospholipid activation of the human TPC2 channel

Ji She, Weizhong Zeng, Jiangtao Guo, Qingfeng Chen, Xiaochen Bai, Youxing Jiang

Research output: Contribution to journalArticle

Abstract

Mammalian two-pore channels (TPCs) regulate the physiological functions of the endolysosome. Here we present cryo-EM structures of human TPC2 (HsTPC2), a phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2)-activated, Na+ selective channel, in the ligand-bound and apo states. The apo structure captures the closed conformation, while the ligand-bound form features the channel in both open and closed conformations. Combined with functional analysis, these structures provide insights into the mechanism of PI(3,5)P2-regulated gating of TPC2, which is distinct from that of TPC1. Specifically, the endolysosome-specific PI(3,5)P2 binds at the first 6-TM and activates the channel - independently of the membrane potential - by inducing a structural change at the pore-lining inner helix (IS6), which forms a continuous helix in the open state but breaks into two segments at Gly317 in the closed state. Additionally, structural comparison to the voltage-dependent TPC1 structure allowed us to identify Ile551 as being responsible for the loss of voltage dependence in TPC2.

Original languageEnglish (US)
JournaleLife
Volume8
DOIs
StatePublished - Mar 12 2019

Fingerprint

Phospholipids
Chemical activation
Conformations
Ligands
Functional analysis
Electric potential
Ion Channels
Linings
Membrane Potentials
phosphatidylinositol 3,5-diphosphate

Keywords

  • cryo-EM
  • human
  • lysosome
  • molecular biophysics
  • phosphoinositide
  • structural biology
  • two-pore channels

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Structural mechanisms of phospholipid activation of the human TPC2 channel. / She, Ji; Zeng, Weizhong; Guo, Jiangtao; Chen, Qingfeng; Bai, Xiaochen; Jiang, Youxing.

In: eLife, Vol. 8, 12.03.2019.

Research output: Contribution to journalArticle

She, Ji ; Zeng, Weizhong ; Guo, Jiangtao ; Chen, Qingfeng ; Bai, Xiaochen ; Jiang, Youxing. / Structural mechanisms of phospholipid activation of the human TPC2 channel. In: eLife. 2019 ; Vol. 8.
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