Key residues in the VDAC2-BAK complex can be targeted to modulate apoptosis

• Published in: PLoS biology 2024-05, Vol.22 (5), p.e3002617
• Main Authors: Yuan, Zheng, van Delft, Mark F, Li, Mark Xiang, Sumardy, Fransisca, Smith, Brian J, Huang, David C S, Lessene, Guillaume, Khakam, Yelena, Jin, Ruitao, He, Sitong, Smith, Nicholas A, Birkinshaw, Richard W, Czabotar, Peter E, Dewson, Grant
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Apoptosis; Bar codes; BAX protein; bcl-2 Homologous Antagonist-Killer Protein - genetics; bcl-2 Homologous Antagonist-Killer Protein - metabolism; Bcl-2 protein; Biological research; Biology and Life Sciences; Biology, Experimental; Cancer; Cancer therapies; Cytosol; Drug development; Fibroblasts; Grooves; HEK293 Cells; Humans; Hydrophobicity; Interfaces; Labeling; Labelling; Libraries; Medicine and Health Sciences; Mitochondria; Mitochondria - metabolism; Mitochondrial membranes; Mutation; Physical Sciences; Protein Binding; Protein-protein interactions; Proteins; Research and Analysis Methods; Residues; Scanning mutagenesis; Survival; Voltage-Dependent Anion Channel 2 - genetics; Voltage-Dependent Anion Channel 2 - metabolism
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3002617

BAK and BAX execute intrinsic apoptosis by permeabilising the mitochondrial outer membrane. Their activity is regulated through interactions with pro-survival BCL-2 family proteins and with non-BCL-2 proteins including the mitochondrial channel protein VDAC2. VDAC2 is important for bringing both BAK and BAX to mitochondria where they execute their apoptotic function. Despite this important function in apoptosis, while interactions with pro-survival family members are well characterised and have culminated in the development of drugs that target these interfaces to induce cancer cell apoptosis, the interaction between BAK and VDAC2 remains largely undefined. Deep scanning mutagenesis coupled with cysteine linkage identified key residues in the interaction between BAK and VDAC2. Obstructive labelling of specific residues in the BH3 domain or hydrophobic groove of BAK disrupted this interaction. Conversely, mutating specific residues in a cytosol-exposed region of VDAC2 stabilised the interaction with BAK and inhibited BAK apoptotic activity. Thus, this VDAC2-BAK interaction site can potentially be targeted to either inhibit BAK-mediated apoptosis in scenarios where excessive apoptosis contributes to disease or to promote BAK-mediated apoptosis for cancer therapy.