Mechanisms of BCL-2 family proteins in mitochondrial apoptosis.

Autor: Czabotar PE; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. czabotar@wehi.edu.au.; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. czabotar@wehi.edu.au., Garcia-Saez AJ; Membrane Biophysics, Institute of Genetics, CECAD, University of Cologne, Cologne, Germany. ana.garcia@uni-koeln.de.
Jazyk: angličtina
Zdroj: Nature reviews. Molecular cell biology [Nat Rev Mol Cell Biol] 2023 Oct; Vol. 24 (10), pp. 732-748. Date of Electronic Publication: 2023 Jul 12.
DOI: 10.1038/s41580-023-00629-4
Abstrakt: The proteins of the BCL-2 family are key regulators of mitochondrial apoptosis, acting as either promoters or inhibitors of cell death. The functional interplay and balance between the opposing BCL-2 family members control permeabilization of the outer mitochondrial membrane, leading to the release of activators of the caspase cascade into the cytosol and ultimately resulting in cell death. Despite considerable research, our knowledge about the mechanisms of the BCL-2 family of proteins remains insufficient, which complicates cell fate predictions and does not allow us to fully exploit these proteins as targets for drug discovery. Detailed understanding of the formation and molecular architecture of the apoptotic pore in the outer mitochondrial membrane remains a holy grail in the field, but new studies allow us to begin constructing a structural model of its arrangement. Recent literature has also revealed unexpected activities for several BCL-2 family members that challenge established concepts of how they regulate mitochondrial permeabilization. In this Review, we revisit the most important advances in the field and integrate them into a new structure-function-based classification of the BCL-2 family members that intends to provide a comprehensive model for BCL-2 action in apoptosis. We close this Review by discussing the potential of drugging the BCL-2 family in diseases characterized by aberrant apoptosis.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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