National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM079179
米国
Welch Foundation
I-1578
米国
Other government
the Cancer Prevention and Research Initiative of Texas
米国
引用
ジャーナル: Elife / 年: 2019 タイトル: Structural mechanisms of phospholipid activation of the human TPC2 channel. 著者: Ji She / Weizhong Zeng / Jiangtao Guo / Qingfeng Chen / Xiao-Chen Bai / Youxing Jiang / 要旨: 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) ...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)P)-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)P-regulated gating of TPC2, which is distinct from that of TPC1. Specifically, the endolysosome-specific PI(3,5)P 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.