7M5A

Crystal Structure of human BAK in complex with W3W5_BID

Summary for 7M5A

• Entry DOI: 10.2210/pdb7m5a/pdb
• Descriptor: Bcl-2 homologous antagonist/killer, BH3-interacting domain death agonist p15 (3 entities in total)
• Functional Keywords: protein-peptide complex, apoptosis
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 21388.94

Authors

Singh, G.,Aggarwal, A.,Moldoveanu, T. (deposition date: 2021-03-23, release date: 2022-01-12, Last modification date: 2024-10-09)

Primary citation

Singh, G.,Guibao, C.D.,Seetharaman, J.,Aggarwal, A.,Grace, C.R.,McNamara, D.E.,Vaithiyalingam, S.,Waddell, M.B.,Moldoveanu, T.
Structural basis of BAK activation in mitochondrial apoptosis initiation.
Nat Commun, 13:250-250, 2022

PubMed 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.

PubMed: 35017502
DOI: 10.1038/s41467-021-27851-y

Experimental method

X-RAY DIFFRACTION (1.5 Å)