Abstract
In eukaryotes, two-pore channels (TPC1-3) comprise a family of ion channels that regulate the conductance of Na+ and Ca2+ ions across cellular membranes. TPC1-3 form endolysosomal channels, but TPC3 can also function in the plasma membrane. TPC1/3 are voltage-gated channels, but TPC2 opens in response to binding endolysosome-specific lipid phosphatidylinositol-3,5-diphosphate (PI(3,5)P2). Filoviruses, such as Ebola, exploit TPC-mediated ion release as a means of escape from the endolysosome during infection. Antagonists that block TPC1/2 channel conductance abrogate filoviral infections. TPC1/2 form complexes with the mechanistic target of rapamycin complex 1 (mTORC1) at the endolysosomal surface that couple cellular metabolic state and cytosolic nutrient concentrations to the control of membrane potential and pH. We determined the X-ray structure of TPC1 from Arabidopsis thaliana (AtTPC1) to 2.87Å resolution–one of the two first reports of a TPC channel structure. Here we summarize these findings and the implications that the structure may have for understanding endolysosomal control mechanisms and their role in human health.
- mTORC1
- Mechanistic target of rapamycin complex 1
- TPC
- Two-pore channel
- PI(3,5)P2
- Phosphatidylinositol-3,5-diphosphate
- AtTPC1
- Arabidopsis thaliana TPC1
- NED19
- Trans-Ned-19
- VSD
- Voltage-sensing domain
- P1
- Pore domain in S5-S6
- P2
- Pore domain in S11-S12
- Cav
- Voltage-gated calcium channel
- Nav
- Voltage-gated sodium channel
- Kv
- Voltage-gated potassium channel
- NTD
- N-terminal domain
- CTD
- C-terminal domain
- EF
- EF-hand domain
- NAADP
- Nicotinic acid adenine dinucleotide phosphate
- PI(4,5)P2
- Phosphatidylinositol-4,5-diphosphate
- DHP
- Dihydropyridine
- PAA
- Phenylalkylamine
- BTZ
- Benzothiazepine
- Caa2+
- Activating Ca2+-ion
- Cai2+
- Inhibitory Ca2+-ion
- fou2
- Fatty acid oxygenation up-regulated 2
- SLC38a9
- Sodium-coupled neutral amino acid transporter 9
- NPC1
- Niemann-Pick C1
- PKA
- Protein kinase A
- PKC
- Protein kinase C
- PKG
- Protein kinase G
- H+
- ATPase - Proton Pump
- 32P
- – Phosphorus-32