6NQ1

Cryo-EM structure of human TPC2 channel in the apo state

Summary for 6NQ1

• Entry DOI: 10.2210/pdb6nq1/pdb
• EMDB information: 0477 0478 0479
• Descriptor: Two pore calcium channel protein 2 (1 entity in total)
• Functional Keywords: channel, lysosome, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 171343.66

Authors

She, J.,Zeng, W.,Guo, J.,Chen, Q.,Bai, X.,Jiang, Y. (deposition date: 2019-01-18, release date: 2019-03-27, Last modification date: 2025-05-14)

Primary citation

She, J.,Zeng, W.,Guo, J.,Chen, Q.,Bai, X.,Jiang, Y.
Structural mechanisms of phospholipid activation of the human TPC2 channel.
Elife, 8:-, 2019

PubMed 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)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.

PubMed: 30860481
DOI: 10.7554/eLife.45222

Experimental method

ELECTRON MICROSCOPY (3.5 Å)