Structural basis of BAK activation in mitochondrial apoptosis initiation

Singh, Geetika; Guibao, Cristina D.; Seetharaman, Jayaraman; Aggarwal, Anup; Grace, Christy R.; McNamara, Dan E.; Vaithiyalingam, Sivaraja; Waddell, M. Brett; Moldoveanu, Tudor

doi:10.1038/s41467-021-27851-y

Title: Structural basis of BAK activation in mitochondrial apoptosis initiation

Journal Article · 11 January 2022 · Nature Communications

DOI: https://doi.org/10.1038/s41467-021-27851-y · OSTI ID:1841221

Singh, Geetika ^[1]; Guibao, Cristina D. ^[2]; Seetharaman, Jayaraman ^[2]; Aggarwal, Anup ^[2]; Grace, Christy R. ^[2]; McNamara, Dan E. ^[2]; Vaithiyalingam, Sivaraja ^[2]; Waddell, M. Brett ^[2];

^[2]

St. Jude Children’s Research Hospital, Memphis, TN (United States); Univ. of Tennessee Health Sciences Center, Memphis, TN (United States)
St. Jude Children’s Research Hospital, Memphis, TN (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: SC0012704

OSTI ID:: 1841221

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 13; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau Rousseaux, Maxime WC; de Haro, Maria; Lasagna-Reeves, Cristian A. eLife, Vol. 5 https://doi.org/10.7554/elife.19809	journal	October 2016

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