TY - JOUR
T1 - Structural mechanisms of phospholipid activation of the human TPC2 channel
AU - She, Ji
AU - Zeng, Weizhong
AU - Guo, Jiangtao
AU - Chen, Qingfeng
AU - Bai, Xiao Chen
AU - Jiang, Youxing
N1 - Funding Information:
We thank N Nguyen for manuscript preparation, and Dr. M X Zhu at University of Texas Health Science Center at Houston for providing clones of animal TPC genes. Single particle cryo-EM data were collected at the University of Texas Southwestern Medical Center Cryo-EM Facility that is funded by the CPRIT Core Facility Support Award RP170644. This work was supported in part by the Howard Hughes Medical Institute (YJ) and by grants from the National Institute of Health (GM079179 to YJ) and the Welch Foundation (Grant I-1578 to YJ). XB is supported by the Cancer Prevention and Research Initiative of Texas and Virginia Murchison Linthicum Scholar in Medical Research fund.
Publisher Copyright:
© She et al.
PY - 2019/3
Y1 - 2019/3
N2 - 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.
AB - 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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U2 - 10.7554/eLife.45222
DO - 10.7554/eLife.45222
M3 - Article
C2 - 30860481
AN - SCOPUS:85063266957
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e45222
ER -