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Structural mechanisms of phospholipid activation of the human TPC2 channel.

<div class='caption-title'>(A) Topology and domain arrangement of an HsTPC2 subunit. (B) Cartoon representation of HsTPC2 with one subunit colored as that in (A) and another in pink. PI(3,5)P2 are shown as yellow sticks. The two EF-hand domains are boxed. (C) Overall structural alignment of HsTPC2 (cyan) and MmTPC1 (pink).</div>
<div class='caption-title'>Sequence alignment of HsTPC2, MmTPC1 and AtTPC1.</div>
<div class='caption-title'>Structure determination of the PI(3,5)P2-bound HsTPC2.</div>
She J, Zeng W, Guo J, Chen Q, Bai XC, Jiang Y
OpenAccess logo Elife 8 (2019)
Related entries: 6nq1, 6nq2

Cited: 65 times
EuropePMC logo PMID: 30860481

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.

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  6. Targeting Two-Pore Channels: Current Progress and Future Challenges. Jin X, Zhang Y, Alharbi A, Hanbashi A, Alhoshani A, Parrington J. Trends Pharmacol Sci 41 582-594 (2020)
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  17. Unveiling the impact of lysosomal ion channels: balancing ion signaling and disease pathogenesis. Jung Y, Kim W, Shin NK, Bae YM, Wie J. Korean J Physiol Pharmacol 27 311-323 (2023)
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  19. Two-Pore Channels Regulate Inter-Organellar Ca2+ Homeostasis in Immune Cells. Steiner P, Arlt E, Boekhoff I, Gudermann T, Zierler S. Cells 11 1465 (2022)
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  22. Endo-Lysosomal Two-Pore Channels and Their Protein Partners. Patel S, Zissimopoulos S, Marchant JS. Handb Exp Pharmacol 278 199-214 (2023)
  23. Endolysosomal transient receptor potential mucolipins and two-pore channels: implications for cancer immunity. Ouologuem L, Bartel K. Front Immunol 15 1389194 (2024)
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