Structural basis of BAK activation in mitochondrial apoptosis initiation.

Autor: Singh G; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.; Integrative Biomedical Sciences Program, University of Tennessee Health Sciences Center, Memphis, TN, 38163, USA., Guibao CD; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA., Seetharaman J; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Aggarwal A; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA., Grace CR; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., McNamara DE; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA., Vaithiyalingam S; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Waddell MB; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Moldoveanu T; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. tudor.moldoveanu@stjude.org.; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA. tudor.moldoveanu@stjude.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jan 11; Vol. 13 (1), pp. 250. Date of Electronic Publication: 2022 Jan 11.
DOI: 10.1038/s41467-021-27851-y
Abstrakt: BCL-2 proteins regulate mitochondrial poration in apoptosis initiation. How the pore-forming BCL-2 Effector BAK is activated remains incompletely understood mechanistically. Here we investigate autoactivation and direct activation by BH3-only proteins, which cooperate to lower BAK threshold in membrane poration and apoptosis initiation. We define in trans BAK autoactivation as the asymmetric "BH3-in-groove" triggering of dormant BAK by active BAK. BAK autoactivation is mechanistically similar to direct activation. The structure of autoactivated BAK BH3-BAK complex reveals the conformational changes leading to helix α1 destabilization, which is a hallmark of BAK activation. Helix α1 is destabilized and restabilized in structures of BAK engaged by rationally designed, high-affinity activating and inactivating BID-like BH3 ligands, respectively. Altogether our data support the long-standing hit-and-run mechanism of BAK activation by transient binding of BH3-only proteins, demonstrating that BH3-induced structural changes are more important in BAK activation than BH3 ligand affinity.
(© 2022. The Author(s).)
Databáze: MEDLINE
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