Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Li, MX; Tan, IKL; Ma, SB; Hockings, C; Kratina, T; Dengler, MA; Alsop, AE; Kluck, RM; Dewson, G.
BAK α6 permits activation by BH3-only proteins and homooligomerization via the canonical hydrophobic groove.
Proc Natl Acad Sci U S A. 2017; 114(29):7629-7634
Doi: 10.1073/pnas.1702453114
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- Co-authors Med Uni Graz
- Dengler Michael
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- Abstract:
- BAK and BAX are the essential effectors of apoptosis because without them a cell is resistant to most apoptotic stimuli. BAK and BAX undergo conformation changes to homooligomerize then permeabilize the mitochondrial outer membrane during apoptosis. How BCL-2 homology 3 (BH3)-only proteins bind to activate BAK and BAX is unclear. We report that BH3-only proteins bind inactive full-length BAK at mitochondria and then dissociate following exposure of the BAK BH3 and BH4 domains before BAK homodimerization. Using a functional obstructive labeling approach, we show that activation of BAK involves important interactions of BH3-only proteins with both the canonical hydrophobic binding groove (α2-5) and α6 at the rear of BAK, with interaction at α6 promoting an open groove to receive a BH3-only protein. Once activated, how BAK homodimers multimerize to form the putative apoptotic pore is unknown. Obstructive labeling of BAK beyond the BH3 domain and hydrophobic groove did not inhibit multimerization and mitochondrial damage, indicating that critical protein-protein interfaces in BAK self-association are limited to the α2-5 homodimerization domain.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Apoptosis -
- BH3 Interacting Domain Death Agonist Protein - metabolism
- Binding Sites -
- Cell Line -
- Cytochromes c - metabolism
- Disulfides - chemistry
- Epitopes - chemistry
- Fibroblasts - metabolism
- Hydrophobic and Hydrophilic Interactions -
- Mice -
- Mice, Inbred C57BL -
- Mitochondria - metabolism
- Mitochondrial Membranes - metabolism
- Protein Binding -
- Protein Domains -
- Protein Interaction Mapping -
- Protein Multimerization -
- bcl-2 Homologous Antagonist-Killer Protein - chemistry
- bcl-2 Homologous Antagonist-Killer Protein - genetics
- bcl-2-Associated X Protein - metabolism
- Find related publications in this database (Keywords)
- apoptosis
- BAK
- BAX
- BH3-only protein
- mitochondria