Bax Inhibitor-1 Is Likely a pH-Sensitive Calcium Leak Channel, Not a H ⁺ /Ca ²⁺ Exchanger

Abstract

The endoplasmic reticulum (ER) plays a key role in the synthesis, folding, and sorting of proteins, and disturbances of this delicate system can cause cell death. The ER also serves as the major intracellular calcium (Ca(2+)) store, and release of Ca(2+) from this store controls diverse cellular functions. At the interface of both these functions of the ER is Bax inhibitor-1 (BI-1), an evolutionarily conserved multifunctional protein that mediates Ca(2+) efflux from the ER and protects against ER stress. Several mechanisms have been proposed to explain how BI-1 might mediate Ca(2+) efflux from the ER. Chang et al. present structural evidence that a bacterial homolog of BI-1, BsYetJ, is a pH-sensitive Ca(2+) leak channel. This finding not only sheds a new light on ER Ca(2+) efflux mediated by BI-1, but also provides a tentative function for other members of the BI-1 protein family.

Golgi anti-apoptotic proteins are evolutionarily conserved ion channels that regulate cell death in plants

“…The homology models based on the structure of BsYetJ suggested that AtGAAPs form transmembrane pores that function as ion channels or exchangers. This is similar to previous proposals that BI-1 (Bultynck et al ., 2014), vGAAPs (Carrara et al ., 2015) and BsYetJ (Chang et al ., 2014) form ion channels or exchangers that mediate Ca 2+ flux across membranes. The aspartate pair (Asp171-Asp195) in BsYetJ is involved in hydrogen bonding responsible for the reversible, pH-dependent transitions between open and closed conformation of BsYetJ that are associated with Ca 2+ leak across the membrane (Chang et al ., 2014).…”

“…This structure revealed seven transmembrane domains (TMDs) and a transmembrane pore capable of assuming open and closed conformations (Chang et al ., 2014). This supports the reported functions of GAAPs and BI-1 as ion channels or antiporters (Kim et al ., 2008; Ahn et al ., 2009; Lee et al ., 2010; Bultynck et al ., 2014; Carrara et al ., 2015). Like BsYetJ, AtGAAPs were predicted to contain seven TMDs ( Supplementary Figure S1 ).…”

Modulation of Autophagy by Calcium Signalosome in Human Disease

“…Indeed, cells have evolved mechanisms to avoid cell death caused by Ca 21 disturbances. Overexpression of cell death suppressor TMBIM6/BI-1 (Bax inhibitor 1, which is a Ca 21 channel), for instance, in conditions of low [Ca 21 ] ER , fundamentally contributes to Ca 21 transfer from the ER to the mitochondria, acting as an ER Ca 21 -leak channel and a sensitizer of IP3-R (Kiviluoto et al, 2012;Bultynck et al, 2014). TMBIM6 also induces autophagy to contribute to the metabolic adaptation of those cells with low [Ca 21 ] ER and low ATP availability (Sano et al, 2012).…”

BAX inhibitor‐1: between stress and survival

“…The Ca 2+ /H + antiporter activities of BI‐1 may be stimulated by interaction with BH4 domains (present in BCL2 and BCLxL) through enhanced protein oligomerization . Nevertheless, no direct evidence has been shown for the association of BI‐1 with proton ions and Bultynck et al commented that such a Ca 2+ /H + antiporter function appears unlikely. They claim the C‐terminal of BI‐1 does not have the biochemical properties to sense acidic pH changes (< 6.8), as its lysine‐rich regions might only be adapted to sense more basic pH changes.…”