Structural basis of BAK activation in mitochondrial apoptosis initiation

Geetika Singh, Cristina D. Guibao, Jayaraman Seetharaman, Anup Aggarwal, Christy R. Grace, Dan E. McNamara, Sivaraja Vaithiyalingam, M. Brett Waddell and Tudor Moldoveanu ()
Additional contact information
Geetika Singh: St. Jude Children’s Research Hospital
Cristina D. Guibao: St. Jude Children’s Research Hospital
Jayaraman Seetharaman: St. Jude Children’s Research Hospital
Anup Aggarwal: St. Jude Children’s Research Hospital
Christy R. Grace: St. Jude Children’s Research Hospital
Dan E. McNamara: St. Jude Children’s Research Hospital
Sivaraja Vaithiyalingam: St. Jude Children’s Research Hospital
M. Brett Waddell: St. Jude Children’s Research Hospital
Tudor Moldoveanu: St. Jude Children’s Research Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-021-27851-y

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