This is desirable in maintaining normal cellular homeostasis but is detrimental to the treatment of tumor cells. Its effects are counteracted by those of Bcl-2, the anti-apoptotic founding member of the Bcl-2 family that is believed to block the action of Bax and thereby promote cell survival. At the MOM, activated Bax forms homo-oligomers that function as pores, resulting in MOMP.
Non-activated Bax is usually found in the cytosol in healthy cells but translocates to the MOM when activated by apoptotic stimuli. cytochrome c) from the intermembrane space. When activated, the pro-apoptotic Bcl-2-associated X protein (Bax) causes mitochondrial outer membrane permeabilization (MOMP), resulting in the release of apoptogenic factors (e.g.
The intrinsic pathway, also known as the mitochondrial pathway, is mediated by proteins of the B-cell CLL/lymphoma-2 (Bcl-2) family, which tightly regulate the integrity of the mitochondrial outer membrane (MOM). hormones) and the intrinsic pathway, which is triggered by intracellular stress factors such as DNA damage, growth factor deprivation and reactive oxygen species. There are two major apoptotic pathways: the extrinsic pathway, which is mediated by the death receptors following their activation by extracellular signals (e.g. Cells undergoing apoptosis display a number of distinctive morphological characteristics, including condensation of the chromatin and fragmentation into apoptotic bodies prior to phagocytosis. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: The authors acknowledge support by SWEDSTRUCT (Swedish Research Council): 2009-3712, URL: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist.Īpoptosis is one of the main types of programmed cell death, and plays a crucial role in multicellular organisms by preserving tissue homeostasis and removing infected and harmful cells. Received: NovemAccepted: MaPublished: April 23, 2013Ĭopyright: © 2013 Wallgren et al. Vertessy, Institute of Enzymology of the Hungarian Academy of Science, Hungary Following detergent removal, the integral membrane protein was found to have been fully reconstituted into a native-like membrane environment, as confirmed by ultracentrifugation and subsequent SDS-PAGE experiments.Ĭitation: Wallgren M, Lidman M, Pedersen A, Brännström K, Karlsson BG, Gröbner G (2013) Reconstitution of the Anti-Apoptotic Bcl-2 Protein into Lipid Membranes and Biophysical Evidence for Its Detergent-Driven Association with the Pro-Apoptotic Bax Protein. In addition, Bcl-2 was able to form mixed micelles with Triton X-100 solubilized neutral phospholipids in the presence of high concentrations of Brij-35 (above its CMC). Upon formation of this protein-protein complex, Bax also prevented the binding of antimycin A 2 (a known inhibitory ligand of Bcl-2) to the Bcl-2 protein, as fluorescence spectroscopy experiments showed. Additional surface plasmon resonance (SPR) measurements confirmed this observation and revealed a high affinity between the Bax and Bcl-2 proteins. Far-UV circular dichroism (CD) spectroscopy was used to detect direct Bcl-2-Bax-interactions in the presence of polyoxyethylene-(23)-lauryl-ether (Brij-35) detergent at a level below its critical micelle concentration (CMC). Here we present the results of a biophysical study in which we investigated the putative interaction of solubilized full-length human Bcl-2 with Bax and the scope for incorporating the former into a native-like lipid environment.
Some studies suggest that Bcl-2 binds directly to and sequesters Bax, while others suggest an indirect process whereby Bcl-2 blocks BH3-only proteins and prevents them from activating Bax. Competing models have been presented that describe how Bcl-2 inhibits the cell-killing activity of Bax, which is common in treatment-resistant tumors where Bcl-2 is overexpressed. However, how they interact at the mitochondrial outer membrane (MOM) and there determine whether the cell will live or be sentenced to death remains unknown. The anti-apoptotic B-cell CLL/lymphoma-2 (Bcl-2) protein and its counterpart, the pro-apoptotic Bcl-2-associated X protein (Bax), are key players in the regulation of the mitochondrial pathway of apoptosis.
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