Bax channel triplet: co-operativity and voltage gating

Abstract

Bax, despite being a cytosolic protein, has the distinct ability to form channels in the mitochondrial outer membrane, which are capable of releasing proteins that initiate the execution phase of apoptosis. When studied in a planar phospholipid membrane system, full-length activated Bax can form conducting entities consistent with linearly organized three-channel units displaying steep voltage-gating (n=14) that rivals that of channels in excitable membranes. In addition, the channels display strong positive co-operativity possibly arising from the charge distribution of the voltage sensors. On the basis of functional behaviour, one of the channels in this functional triplet is oriented in the opposite direction to the others often resulting in conflicts between the effects of the electric field and the positive co-operativity of adjacent channels. The closure of the first channel occurs at positive potentials and this permits the second to close, but at negative potentials. The closure of the second channel in turn permits closure of the third, but at positive potentials. Positive co-operativity manifests itself in a number of ways including the second and the third channels opening virtually simultaneously. This extraordinary behaviour must have important, although as yet undefined, physiological roles.

JNK3 phosphorylates Bax protein and induces ability to form pore on bilayer lipid membrane

“…Furthermore, it is known that during apoptosis JNKs phosphorylated Bax promotes the release of cytochrome c into the cytosol but the mechanism how JNKs phosphorylated Bax interacts with the outer mitochondrial membrane and release it is not clear. One of the possibilities is that it forms mitochondrial membrane ion pores [25] , [26] , [27] , [28] . In vitro studies on model membranes like artificial bilayer lipid membranes (BLMs) provide an effective means to understand the mechanism of action of membrane active molecules [29] .…”