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. 2020 Jan 24;9:e44525. doi: 10.7554/eLife.44525

Figure 11. Schematic overview for the Bim CTS pro-apoptotic function Interactions between BimL (blue), effector protein Bax (red) and Bcl-XL (green) are shown at mitochondria of unprimed and primed cells as indicated.

Figure 11.

Mutations of the Bim CTS are shown as a red or yellow star. Direction of protein flow into complexes indicated by lengths of the equilibria arrows is based on the Kds measured for the binding interactions (Figure 6B), using the approximate cellular concentrations of the various proteins and activity assays with liposomes and mitochondria. (A) In unprimed cells the direct activation of Bax is the main function of Bim for inducing apoptosis. Comparison of BimL-I125E with BimL-L129E, BimL-I132E, and BimL-dCTS shows that the CTS, not membrane binding controls the activation of Bax by BimL (Figure 6B). BimL binds membranes and can activate Bax. BimL-I125E (yellow star) has no detectable membrane-binding activity but still binds to and activates Bax, albeit with reduced activity compared to BimL (Figure 6B). At physiologically relevant concentrations BimL-L129E, BimL-I132E, and BimL-dCTS do not activate Bax and do not bind to membranes. However unlike BimL-dCTS. BimL-L129E and BimL-I132E binding to Bax is not reduced enough to account for the loss in Bax activation and membrane permeabilization suggesting these two residues are involved in activating Bax. (B) In primed cells, one or more pro-apoptotic proteins (activated Bax/Bak and/or a Bax/Bak-activating BH3-protein) are sequestered by anti-apoptotic proteins at the MOM. For simplicity only active Bax is shown. Depending on the amount of active pro-apoptotic protein sequestered and the amount of free inactive Bax and or Bak in the cell, BimL may initiate apoptosis primarily by inhibiting anti-apoptotic proteins or by activating Bax and inhibiting anti-apoptotic proteins. The Bim CTS is not required for binding to and inhibiting anti-apoptotic proteins as BimL-L129E, BimL-I132E, and BimL-dCTS bind to anti-apoptotic proteins such as Bcl-XL and release both pro-apoptotic BH3-proteins and Bax (Figure 5 and Figure 6B), thus enabling killing of primed cells.