Review Article | Published:

Topology of active, membrane-embedded Bax in the context of a toroidal pore

Cell Death & Differentiationvolume 25pages17171731 (2018) | Download Citation

Abstract

Bax is a Bcl-2 protein critical for apoptosis induction. In healthy cells, Bax is mostly a monomeric, cytosolic protein, while upon apoptosis initiation it inserts into the outer mitochondrial membrane, oligomerizes, and forms pores that release proapoptotic factors like Cytochrome c into the cytosol. The structures of active Bax and its homolog Bak are only partially understood and the topology of the proteins with respect to the membrane bilayer is controversially described in the literature. Here, we systematically review and examine the protein–membrane, protein–water, and protein–protein contacts of the nine helices of active Bax and Bak, and add a new set of topology data obtained by fluorescence and EPR methods. We conclude based on the consistent part of the datasets that the core/dimerization domain of Bax (Bak) is water exposed with only helices 4 and 5 in membrane contact, whereas the piercing/latch domain is in peripheral membrane contact, with helix 9 being transmembrane. Among the available structural models, those considering the dimerization/core domain at the rim of a toroidal pore are the most plausible to describe the active state of the proteins, although the structural flexibility of the piercing/latch domain does not allow unambiguous discrimination between the existing models.

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Acknowledgements

This work was supported by the DFG Priority Program SPP1601 “New Frontiers in Sensitivity in EPR Spectroscopy” (EB and TEA), the DFG grant BO 3000/5-1 and INST 130/972-1 FUGG (EB), the European Research Council (ERC-2012-StG 309966; SB, CS, and AJG-S), the Forschergruppe 2036 (SB, CS, and AJG-S), and the Cluster of Excellence RESOLV (EXC 1069; SB and EB) funded by the Deutsche Forschungsgemeinschaft. The ESEEM data were recorded in the laboratory of Robert Bittl, FU Berlin. EB would like to thank Gunnar Jeschke and ETH Zurich for the Matlab script used for ESEEM data analysis and the home-made Q-band resonator.

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  1. Department of Chemistry and Biochemistry, Ruhr-University Bochum, Universitätsstr. 150, 44801, Bochum, Germany

    • Stephanie Bleicken
    • , Tufa E. Assafa
    •  & Enrica Bordignon
  2. ZEMOS, Ruhr-University Bochum, Universitätsstr. 150, 44801, Bochum, Germany

    • Stephanie Bleicken
  3. Department of Physics, Freie Universität Berlin, Arnimallee 14, 14195, Berlin, Germany

    • Tufa E. Assafa
    • , Alice Wittig
    •  & Enrica Bordignon
  4. Interfaculty Institute of Biochemistry, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 4, 72076, Tübingen, Germany

    • Stephanie Bleicken
    • , Carolin Stegmueller
    •  & Ana J. Garcia-Saez

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The authors declare that they have no conflict of interest.

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Correspondence to Stephanie Bleicken or Enrica Bordignon.

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https://doi.org/10.1038/s41418-018-0184-6