PMID- 19917256
OWN - NLM
STAT- MEDLINE
DCOM- 20100106
LR  - 20220330
IS  - 1097-4164 (Electronic)
IS  - 1097-2765 (Print)
IS  - 1097-2765 (Linking)
VI  - 36
IP  - 3
DP  - 2009 Nov 13
TI  - Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial 
      apoptosis.
PG  - 487-99
LID - 10.1016/j.molcel.2009.09.030 [doi]
AB  - While activation of BAX/BAK by BH3-only molecules (BH3s) is essential for 
      mitochondrial apoptosis, the underlying mechanisms remain unsettled. Here we 
      demonstrate that BAX undergoes stepwise structural reorganization leading to 
      mitochondrial targeting and homo-oligomerization. The alpha1 helix of BAX keeps 
      the alpha9 helix engaged in the dimerization pocket, rendering BAX as a monomer 
      in cytosol. The activator BH3s, tBID/BIM/PUMA, attack and expose the alpha1 helix 
      of BAX, resulting in secondary disengagement of the alpha9 helix and thereby 
      mitochondrial insertion. Activator BH3s remain associated with the N-terminally 
      exposed BAX through the BH1 domain to drive homo-oligomerization. BAK, an 
      integral mitochondrial membrane protein, has bypassed the first activation step, 
      explaining why its killing kinetics are faster than those of BAX. Furthermore, 
      death signals initiated at ER induce BIM and PUMA to activate mitochondrial 
      apoptosis. Accordingly, deficiency of Bim/Puma impedes ER stress-induced BAX/BAK 
      activation and apoptosis. Our study provides mechanistic insights regarding the 
      spatiotemporal execution of BAX/BAK-governed cell death.
FAU - Kim, Hyungjin
AU  - Kim H
AD  - Molecular Oncology, Department of Medicine, Washington University School of 
      Medicine, St. Louis, MO 63110, USA.
FAU - Tu, Ho-Chou
AU  - Tu HC
FAU - Ren, Decheng
AU  - Ren D
FAU - Takeuchi, Osamu
AU  - Takeuchi O
FAU - Jeffers, John R
AU  - Jeffers JR
FAU - Zambetti, Gerard P
AU  - Zambetti GP
FAU - Hsieh, James J-D
AU  - Hsieh JJ
FAU - Cheng, Emily H-Y
AU  - Cheng EH
LA  - eng
GR  - R01 GM083159/GM/NIGMS NIH HHS/United States
GR  - R01CA125562/CA/NCI NIH HHS/United States
GR  - R01 CA125562-02/CA/NCI NIH HHS/United States
GR  - R01 CA125562/CA/NCI NIH HHS/United States
GR  - P30CA21765/CA/NCI NIH HHS/United States
GR  - R01 CA125562-03/CA/NCI NIH HHS/United States
GR  - P30 CA021765/CA/NCI NIH HHS/United States
GR  - R01 CA125562-01A1/CA/NCI NIH HHS/United States
GR  - K01CA98320/CA/NCI NIH HHS/United States
GR  - K01 CA098320/CA/NCI NIH HHS/United States
GR  - R01GM083159/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cell
JT  - Molecular cell
JID - 9802571
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BH3 Interacting Domain Death Agonist Protein)
RN  - 0 (Bak1 protein, mouse)
RN  - 0 (Bax protein, mouse)
RN  - 0 (Bcl-2-Like Protein 11)
RN  - 0 (Bcl2l11 protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0 (PUMA protein, mouse)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (bcl-2 Homologous Antagonist-Killer Protein)
RN  - 0 (bcl-2-Associated X Protein)
RN  - 11089-65-9 (Tunicamycin)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 67526-95-8 (Thapsigargin)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - H88EPA0A3N (Staurosporine)
SB  - IM
CIN - Mol Cell. 2009 Nov 13;36(3):353-4. PMID: 19917244
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Apoptosis Regulatory Proteins/genetics/*metabolism
MH  - BH3 Interacting Domain Death Agonist Protein/genetics/*metabolism
MH  - Bcl-2-Like Protein 11
MH  - Cells, Cultured
MH  - Etoposide/pharmacology
MH  - Fibroblasts/cytology/drug effects/metabolism
MH  - Green Fluorescent Proteins/genetics/metabolism
MH  - Immunoblotting
MH  - Immunoprecipitation
MH  - Membrane Proteins/genetics/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Microscopy, Fluorescence
MH  - Mitochondria/metabolism
MH  - Models, Biological
MH  - Mutation
MH  - Protein Binding/drug effects
MH  - Protein Multimerization
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Staurosporine/pharmacology
MH  - Thapsigargin/pharmacology
MH  - Tumor Suppressor Proteins/genetics/*metabolism
MH  - Tunicamycin/pharmacology
MH  - bcl-2 Homologous Antagonist-Killer Protein/chemistry/genetics/*metabolism
MH  - bcl-2-Associated X Protein/chemistry/genetics/*metabolism
PMC - PMC3163439
MID - NIHMS150597
EDAT- 2009/11/18 06:00
MHDA- 2010/01/07 06:00
PMCR- 2011/08/29
CRDT- 2009/11/18 06:00
PHST- 2009/03/03 00:00 [received]
PHST- 2009/06/30 00:00 [revised]
PHST- 2009/08/21 00:00 [accepted]
PHST- 2009/11/18 06:00 [entrez]
PHST- 2009/11/18 06:00 [pubmed]
PHST- 2010/01/07 06:00 [medline]
PHST- 2011/08/29 00:00 [pmc-release]
AID - S1097-2765(09)00690-X [pii]
AID - 10.1016/j.molcel.2009.09.030 [doi]
PST - ppublish
SO  - Mol Cell. 2009 Nov 13;36(3):487-99. doi: 10.1016/j.molcel.2009.09.030.