The C terminus of bax inhibitor-1 forms a Ca 2+-permeable channel pore

Geert Bultynck, Santeri Kiviluoto, Nadine Henke, Hristina Ivanova, Lars Schneider, Volodymyr Rybalchenko, Tomas Luyten, Koen Nuyts, Wim De Borggraeve, Ilya Bezprozvanny, Jan B. Parys, Humbert De Smedt, Ludwig Missiaen, Axel Methner

Research output: Contribution to journalArticle

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Abstract

Bax inhibitor-1 (BI-1) is a multitransmembrane domain-spanning endoplasmic reticulum (ER)-located protein that is evolutionarily conserved and protects against apoptosis and ER stress. Furthermore, BI-1 is proposed to modulate ER Ca 2+homeostasis by acting as a Ca 2+-leak channel. Based on experimental determination of the BI-1 topology, we propose that its C terminus forms a Ca 2+ pore responsible for its Ca 2+-leak properties. We utilized a set of C-terminal peptides to screen for Ca 2+ leak activity in unidirectional 45Ca 2+-flux experiments and identified an α-helical 20-amino acid peptide causing Ca 2+leak from the ER. The Ca 2+ leak was independent of endogenous ER Ca 2+-release channels or other Ca 2+-leak mechanisms, namely translocons and presenilins. The Ca 2+-permeating property of the peptide was confirmed in lipid-bilayer experiments. Using mutant peptides, we identified critical residues responsible for the Ca 2+-leak properties of this BI-1 peptide, including a series of critical negatively charged aspartate residues. Using peptides corresponding to the equivalent BI-1 domain from various organisms, we found that the Ca 2+-leak properties were conserved among animal, but not plant and yeast orthologs. By mutating one of the critical aspartate residues in the proposed Ca 2+-channel pore in full-length BI-1, we found that Asp-213 was essential for BI-1-dependent ER Ca 2+leak. Thus, we elucidated residues critically important for BI-1-mediated Ca 2+ leak and its potential channel pore. Remarkably, one of these residues was not conserved among plant and yeast BI-1 orthologs, indicating that the ER Ca 2+-leak properties of BI-1 are an added function during evolution.

Original languageEnglish (US)
Pages (from-to)2544-2557
Number of pages14
JournalJournal of Biological Chemistry
Volume287
Issue number4
DOIs
StatePublished - Jan 20 2012

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Endoplasmic Reticulum
Peptides
Aspartic Acid
Yeast
Yeasts
Presenilins
Endoplasmic Reticulum Stress
Lipid bilayers
Lipid Bilayers
Animals
Homeostasis
Experiments
Topology
Apoptosis
Fluxes
Amino Acids
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Bultynck, G., Kiviluoto, S., Henke, N., Ivanova, H., Schneider, L., Rybalchenko, V., ... Methner, A. (2012). The C terminus of bax inhibitor-1 forms a Ca 2+-permeable channel pore. Journal of Biological Chemistry, 287(4), 2544-2557. https://doi.org/10.1074/jbc.M111.275354

The C terminus of bax inhibitor-1 forms a Ca 2+-permeable channel pore. / Bultynck, Geert; Kiviluoto, Santeri; Henke, Nadine; Ivanova, Hristina; Schneider, Lars; Rybalchenko, Volodymyr; Luyten, Tomas; Nuyts, Koen; De Borggraeve, Wim; Bezprozvanny, Ilya; Parys, Jan B.; De Smedt, Humbert; Missiaen, Ludwig; Methner, Axel.

In: Journal of Biological Chemistry, Vol. 287, No. 4, 20.01.2012, p. 2544-2557.

Research output: Contribution to journalArticle

Bultynck, G, Kiviluoto, S, Henke, N, Ivanova, H, Schneider, L, Rybalchenko, V, Luyten, T, Nuyts, K, De Borggraeve, W, Bezprozvanny, I, Parys, JB, De Smedt, H, Missiaen, L & Methner, A 2012, 'The C terminus of bax inhibitor-1 forms a Ca 2+-permeable channel pore', Journal of Biological Chemistry, vol. 287, no. 4, pp. 2544-2557. https://doi.org/10.1074/jbc.M111.275354
Bultynck, Geert ; Kiviluoto, Santeri ; Henke, Nadine ; Ivanova, Hristina ; Schneider, Lars ; Rybalchenko, Volodymyr ; Luyten, Tomas ; Nuyts, Koen ; De Borggraeve, Wim ; Bezprozvanny, Ilya ; Parys, Jan B. ; De Smedt, Humbert ; Missiaen, Ludwig ; Methner, Axel. / The C terminus of bax inhibitor-1 forms a Ca 2+-permeable channel pore. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 4. pp. 2544-2557.
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AU - Schneider, Lars

AU - Rybalchenko, Volodymyr

AU - Luyten, Tomas

AU - Nuyts, Koen

AU - De Borggraeve, Wim

AU - Bezprozvanny, Ilya

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