Publication Date:
2003-07-26
Description:
The multidomain proapoptotic molecules BAK or BAX are required to initiate the mitochondrial pathway of apoptosis. How cells maintain the potentially lethal proapoptotic effector BAK in a monomeric inactive conformation at mitochondria is unknown. In viable cells, we found BAK complexed with mitochondrial outer-membrane protein VDAC2, a VDAC isoform present in low abundance that interacts specifically with the inactive conformer of BAK. Cells deficient in VDAC2, but not cells lacking the more abundant VDAC1, exhibited enhanced BAK oligomerization and were more susceptible to apoptotic death. Conversely, overexpression of VDAC2 selectively prevented BAK activation and inhibited the mitochondrial apoptotic pathway. Death signals activate "BH3-only" molecules such as tBID, BIM, or BAD, which displace VDAC2 from BAK, enabling homo-oligomerization of BAK and apoptosis. Thus, VDAC2, an isoform restricted to mammals, regulates the activity of BAK and provides a connection between mitochondrial physiology and the core apoptotic pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheng, Emily H Y -- Sheiko, Tatiana V -- Fisher, Jill K -- Craigen, William J -- Korsmeyer, Stanley J -- NS42319/NS/NINDS NIH HHS/ -- R37CA50239/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2003 Jul 25;301(5632):513-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12881569" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*Apoptosis
;
BH3 Interacting Domain Death Agonist Protein
;
Biopolymers
;
Carrier Proteins/metabolism/pharmacology
;
Cell Line
;
Cells, Cultured
;
Etoposide/pharmacology
;
Humans
;
Intracellular Membranes/metabolism
;
Jurkat Cells
;
Membrane Proteins/chemistry/genetics/*metabolism
;
Mice
;
Mice, Inbred C57BL
;
Mitochondria/*metabolism
;
Mitochondria, Liver/metabolism
;
Porins/genetics/isolation & purification/*metabolism
;
Protein Binding
;
Protein Conformation
;
Protein Structure, Tertiary
;
Proto-Oncogene Proteins/metabolism
;
*Proto-Oncogene Proteins c-bcl-2
;
Recombinant Proteins/pharmacology
;
Staurosporine/pharmacology
;
Voltage-Dependent Anion Channel 1
;
Voltage-Dependent Anion Channel 2
;
Voltage-Dependent Anion Channels
;
bcl-2 Homologous Antagonist-Killer Protein
;
bcl-2-Associated X Protein
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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