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

Autor: Yuan Z; Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Australia., van Delft MF; Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Australia., Li MX; Peter MacCallum Cancer Centre, Parkville, Melbourne, Australia., Sumardy F; Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia., Smith BJ; La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia., Huang DCS; Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Australia., Lessene G; Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Australia.; Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Melbourne, Australia., Khakam Y; Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia., Jin R; La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.; Research School of Biology, Australian National University, Canberra, Australia., He S; La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia., Smith NA; La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia., Birkinshaw RW; Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Australia., Czabotar PE; Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Australia., Dewson G; Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Australia.
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2024 May 02; Vol. 22 (5), pp. e3002617. Date of Electronic Publication: 2024 May 02 (Print Publication: 2024).
DOI: 10.1371/journal.pbio.3002617
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Yuan et al. 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.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje