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Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design.

Brouwer JM, Lan P, Cowan AD, Bernardini JP, Birkinshaw RW, van Delft MF, Sleebs BE, Robin AY, Wardak A, Tan IK, Reljic B, Lee EF, Fairlie WD, Call MJ, Smith BJ, Dewson G, Lessene G, Colman PM, Czabotar PE
Mol Cell 68 659-672.e9 (2017)
Related entries: 5vwv, 5vww, 5vwx, 5vwy, 5vwz, 5vx0, 5vx2, 5vx3

Cited: 31 times
EuropePMC logo PMID: 29149594

Abstract

Certain BH3-only proteins transiently bind and activate Bak and Bax, initiating their oligomerization and the permeabilization of the mitochondrial outer membrane, a pivotal step in the mitochondrial pathway to apoptosis. Here we describe the first crystal structures of an activator BH3 peptide bound to Bak and illustrate their use in the design of BH3 derivatives capable of inhibiting human Bak on mitochondria. These BH3 derivatives compete for the activation site at the canonical groove, are the first engineered inhibitors of Bak activation, and support the role of key conformational transitions associated with Bak activation.

Articles - 5vx1 mentioned but not cited (1)

  1. Structure of the BAK-activating antibody 7D10 bound to BAK reveals an unexpected role for the α1-α2 loop in BAK activation. Robin AY, Miller MS, Iyer S, Shi MX, Wardak AZ, Lio D, Smith NA, Smith BJ, Birkinshaw RW, Czabotar PE, Kluck RM, Colman PM. Cell Death Differ 29 1757-1768 (2022)


Reviews citing this publication (12)

  1. Mitochondria as multifaceted regulators of cell death. Bock FJ, Tait SWG. Nat Rev Mol Cell Biol 21 85-100 (2020)
  2. BAX, BAK, and BOK: A Coming of Age for the BCL-2 Family Effector Proteins. Moldoveanu T, Czabotar PE. Cold Spring Harb Perspect Biol 12 a036319 (2020)
  3. Physiological and pharmacological modulation of BAX. Spitz AZ, Gavathiotis E. Trends Pharmacol Sci 43 206-220 (2022)
  4. The third model of Bax/Bak activation: a Bcl-2 family feud finally resolved? Luo X, O'Neill KL, Huang K. F1000Res 9 F1000 Faculty Rev-935 (2020)
  5. The Structural Biology of Bcl-xL. Lee EF, Fairlie WD. Int J Mol Sci 20 E2234 (2019)
  6. Neuronal cell life, death, and axonal degeneration as regulated by the BCL-2 family proteins. Pemberton JM, Pogmore JP, Andrews DW. Cell Death Differ 28 108-122 (2021)
  7. Too much death can kill you: inhibiting intrinsic apoptosis to treat disease. Li K, van Delft MF, Dewson G. EMBO J 40 e107341 (2021)
  8. The Mysteries around the BCL-2 Family Member BOK. Shalaby R, Flores-Romero H, García-Sáez AJ. Biomolecules 10 E1638 (2020)
  9. VDAC2 and the BCL-2 family of proteins. Yuan Z, Dewson G, Czabotar PE, Birkinshaw RW. Biochem Soc Trans 49 2787-2795 (2021)
  10. Mechanisms of BCL-2 family proteins in mitochondrial apoptosis. Czabotar PE, Garcia-Saez AJ. Nat Rev Mol Cell Biol 24 732-748 (2023)
  11. Protein-protein and protein-lipid interactions of pore-forming BCL-2 family proteins in apoptosis initiation. Sekar G, Ojoawo A, Moldoveanu T. Biochem Soc Trans 50 1091-1103 (2022)
  12. Structural Details of BH3 Motifs and BH3-Mediated Interactions: an Updated Perspective. Sora V, Papaleo E. Front Mol Biosci 9 864874 (2022)

Articles citing this publication (18)

  1. CASTp 3.0: computed atlas of surface topography of proteins. Tian W, Chen C, Lei X, Zhao J, Liang J. Nucleic Acids Res 46 W363-W367 (2018)
  2. Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy. Bernardini JP, Brouwer JM, Tan IK, Sandow JJ, Huang S, Stafford CA, Bankovacki A, Riffkin CD, Wardak AZ, Czabotar PE, Lazarou M, Dewson G. EMBO J 38 e99916 (2019)
  3. Intrinsic Instability of BOK Enables Membrane Permeabilization in Apoptosis. Zheng JH, Grace CR, Guibao CD, McNamara DE, Llambi F, Wang YM, Chen T, Moldoveanu T. Cell Rep 23 2083-2094.e6 (2018)
  4. A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis. van Delft MF, Chappaz S, Khakham Y, Bui CT, Debrincat MA, Lowes KN, Brouwer JM, Grohmann C, Sharp PP, Dagley LF, Li L, McArthur K, Luo MX, Chin HS, Fairlie WD, Lee EF, Segal D, Duflocq S, Lessene R, Bernard S, Peilleron L, Nguyen T, Miles C, Wan SS, Lane RM, Wardak A, Lackovic K, Colman PM, Sandow JJ, Webb AI, Czabotar PE, Dewson G, Watson KG, Huang DCS, Lessene G, Kile BT. Nat Chem Biol 15 1057-1066 (2019)
  5. Characterization of an alternative BAK-binding site for BH3 peptides. Ye K, Meng WX, Sun H, Wu B, Chen M, Pang YP, Gao J, Wang H, Wang J, Kaufmann SH, Dai H. Nat Commun 11 3301 (2020)
  6. Qiang-Xin 1 Formula Prevents Sepsis-Induced Apoptosis in Murine Cardiomyocytes by Suppressing Endoplasmic Reticulum- and Mitochondria-Associated Pathways. Xu X, Liu Q, He S, Zhao J, Wang N, Han X, Guo Y. Front Pharmacol 9 818 (2018)
  7. High-resolution analysis of the conformational transition of pro-apoptotic Bak at the lipid membrane. Sperl LE, Rührnößl F, Schiller A, Haslbeck M, Hagn F. EMBO J 40 e107159 (2021)
  8. Separase-triggered apoptosis enforces minimal length of mitosis. Hellmuth S, Stemmann O. Nature 580 542-547 (2020)
  9. Structural basis of BAK activation in mitochondrial apoptosis initiation. Singh G, Guibao CD, Seetharaman J, Aggarwal A, Grace CR, McNamara DE, Vaithiyalingam S, Waddell MB, Moldoveanu T. Nat Commun 13 250 (2022)
  10. lncRNA MIRF Promotes Cardiac Apoptosis through the miR-26a-Bak1 Axis. Su X, Lv L, Li Y, Fang R, Yang R, Li C, Li T, Zhu D, Li X, Zhou Y, Shan H, Liang H. Mol Ther Nucleic Acids 20 841-850 (2020)
  11. Apoptotic mitochondrial poration by a growing list of pore-forming BCL-2 family proteins. Moldoveanu T. Bioessays 45 e2200221 (2023)
  12. Small molecule SJ572946 activates BAK to initiate apoptosis. Sekar G, Singh G, Qin X, Guibao CD, Schwam B, Inde Z, Grace CR, Zhang W, Slavish PJ, Lin W, Chen T, Lee RE, Rankovic Z, Sarosiek K, Moldoveanu T. iScience 25 105064 (2022)
  13. Computational Approaches for Identification of Potential Plant Bioactives as Novel G6PD Inhibitors Using Advanced Tools and Databases. Aldossari RM, Ali A, Rehman MU, Rashid S, Ahmad SB. Molecules 28 3018 (2023)
  14. Peptides from human BNIP5 and PXT1 and non-native binders of pro-apoptotic BAK can directly activate or inhibit BAK-mediated membrane permeabilization. Aguilar F, Yu S, Grant RA, Swanson S, Ghose D, Su BG, Sarosiek KA, Keating AE. Structure 31 265-281.e7 (2023)
  15. The Bak core dimer focuses triacylglycerides in the membrane. Smith NA, Wardak AZ, Cowan AD, Colman PM, Czabotar PE, Smith BJ. Biophys J 121 347-360 (2022)
  16. Parkin-mediated ubiquitination inhibits BAK apoptotic activity by blocking its canonical hydrophobic groove. Cheng P, Hou Y, Bian M, Fang X, Liu Y, Rao Y, Cao S, Liu Y, Zhang S, Chen Y, Dong X, Liu Z. Commun Biol 6 1260 (2023)
  17. Structural basis for proapoptotic activation of Bak by the noncanonical BH3-only protein Pxt1. Lim D, Choe SH, Jin S, Lee S, Kim Y, Shin HC, Choi JS, Oh DB, Kim SJ, Seo J, Ku B. PLoS Biol 21 e3002156 (2023)
  18. Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival Bcl-2 family proteins. Wang H, Guo M, Wei H, Chen Y. Comput Struct Biotechnol J 21 3760-3767 (2023)


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