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Cellular and Molecular Life Sciences

, Volume 75, Issue 20, pp 3803–3815 | Cite as

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

  • Sonja A. Kirsch
  • Andreas Kugemann
  • Armando Carpaneto
  • Rainer A. BöckmannEmail author
  • Petra DietrichEmail author
Original Article
  • 406 Downloads

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 

Abbreviations

PI(3,5)P2

Phosphatidylinositol-(3,5)-bisphosphate

POPC

1-Palmitoyl-2-oleoyl phosphatidylcholine

MD

Molecular dynamics

CG

Coarse-grained

Notes

Acknowledgements

This work was supported by the Research Training Group 1962 (to RAB and PD) from the Deutsche Forschungsgemeinschaft and by 2015795S5W funding to AC from the Italian Ministry of Education, University and Research. We would like to thank Joachim Scholz-Starke and Margherita Festa (Genova) for supervision of AK during part of his experiments.

Author contributions

RAB and PD designed and directed research of the simulations and functional analysis, respectively. SAK set up the homology model, and performed CG and atomistic simulations and the related analysis. AK performed cloning, site-directed mutagenesis, functional expression and patch-clamp analysis in plant vacuoles and analyzed the data; AC hosted AK during a laboratory stay to conduct part of the experiments and helped analyzing the data. SAK, PD, RAB, AK, and AC wrote the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

Supplementary material

18_2018_2829_MOESM1_ESM.pdf (12.2 mb)
Supplementary material 1 (PDF 12533 kb)

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Computational Biology, Department of BiologyFriedrich-Alexander Universität Erlangen-NürnbergErlangenGermany
  2. 2.Molecular Plant Physiology, Department of BiologyFriedrich-Alexander Universität Erlangen-NürnbergErlangenGermany
  3. 3.Institute of Biophysics, National Research CouncilGenoaItaly
  4. 4.Department of Earth, Environment and Life Sciences-DISTAVUniversity of GenoaGenoaItaly

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