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 journalArticlepeer-review

71 Scopus citations


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
Issue number4
StatePublished - Jan 20 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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