Structural mechanisms of phospholipid activation of the human TPC2 channel

eLife - Tập 8
Ji She1,2, Weizhong Zeng1,2,3, Jiangtao Guo4,5, Yi‐Ping Phoebe Chen1,2,3, Xiao‐chen Bai1,6, Youxing Jiang1,2,3
1Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States;
2Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States;
3Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States;
4Department of Biophysics, Zhejiang University School of Medicine, Hangzhou, China
5Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
6Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, United States

Tóm tắt

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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