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Cell Mol Life Sci. 2018 Oct;75(20):3803-3815. doi: 10.1007/s00018-018-2829-5. Epub 2018 Apr 28.

Phosphatidylinositol-3,5-bisphosphate lipid-binding-induced activation of the human two-pore channel 2.

Author information

1
Computational Biology, Department of Biology, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
2
Molecular Plant Physiology, Department of Biology, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
3
Institute of Biophysics, National Research Council, Genoa, Italy.
4
Department of Earth, Environment and Life Sciences-DISTAV, University of Genoa, Genoa, Italy.
5
Computational Biology, Department of Biology, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany. rainer.boeckmann@fau.de.
6
Molecular Plant Physiology, Department of Biology, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany. petra.dietrich@fau.de.

Abstract

Mammalian two-pore channels (TPCs) are activated by the low-abundance membrane lipid phosphatidyl-(3,5)-bisphosphate (PI(3,5)P2) present in the endo-lysosomal system. Malfunction of human TPC1 or TPC2 (hTPC) results in severe organellar storage diseases and membrane trafficking defects. Here, we compared the lipid-binding characteristics of hTPC2 and of the PI(3,5)P2-insensitive TPC1 from the model plant Arabidopsis thaliana. Combination of simulations with functional analysis of channel mutants revealed the presence of an hTPC2-specific lipid-binding pocket mutually formed by two channel regions exposed to the cytosolic side of the membrane. We showed that PI(3,5)P2 is simultaneously stabilized by positively charged amino acids (K203, K204, and K207) in the linker between transmembrane helices S4 and S5 and by S322 in the cytosolic extension of S6. We suggest that PI(3,5)P2 cross links two parts of the channel, enabling their coordinated movement during channel gating.

KEYWORDS:

Electrophysiology; Homology model; Ion channel; Ligand-binding; Molecular dynamics simulation; Site-directed mutagenesis

PMID:
29705952
DOI:
10.1007/s00018-018-2829-5
[Indexed for MEDLINE]

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