BIM-Mediated Membrane Insertion of the BAK Pore Domain Is an Essential Requirement for Apoptosis
BAK activation represents a key step during apoptosis, but how it converts into a mitochondria-permeabilizing pore remains unclear. By further delineating the structural rearrangements involved, we reveal that BAK activation progresses through a series of independent steps: BH3-domain exposure, N-te...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-10-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124713005184 |
| _version_ | 1818449648259432448 |
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| author | Kathrin Weber Nicholas Harper John Schwabe Gerald M. Cohen |
| author_facet | Kathrin Weber Nicholas Harper John Schwabe Gerald M. Cohen |
| author_sort | Kathrin Weber |
| collection | DOAJ |
| description | BAK activation represents a key step during apoptosis, but how it converts into a mitochondria-permeabilizing pore remains unclear. By further delineating the structural rearrangements involved, we reveal that BAK activation progresses through a series of independent steps: BH3-domain exposure, N-terminal change, oligomerization, and membrane insertion. Employing a “BCL-XL-addiction” model, we show that neutralization of BCL-XL by the BH3 mimetic ABT-737 resulted in death only when cells were reconstituted with BCL-XL:BAK, but not BCL-2/ BCL-XL:BIM complexes. Although this resembles the indirect model, release of BAK from BCL-XL did not result in spontaneous adoption of the pore conformation. Commitment to apoptosis required association of the direct activator BIM with oligomeric BAK promoting its conversion to a membrane-inserted pore. The sequential nature of this cascade provides multiple opportunities for other BCL-2 proteins to interfere with or promote BAK activation and unites aspects of the indirect and direct activation models. |
| first_indexed | 2024-12-14T20:38:45Z |
| format | Article |
| id | doaj.art-c1f36d1c70384cf2ae99c9cbc7837626 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-14T20:38:45Z |
| publishDate | 2013-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c1f36d1c70384cf2ae99c9cbc78376262022-12-21T22:48:20ZengElsevierCell Reports2211-12472013-10-015240942010.1016/j.celrep.2013.09.010BIM-Mediated Membrane Insertion of the BAK Pore Domain Is an Essential Requirement for ApoptosisKathrin Weber0Nicholas Harper1John Schwabe2Gerald M. Cohen3MRC Toxicology Unit, University of Leicester, Hodgkin Building, Leicester LE1 9HN, UKMRC Toxicology Unit, University of Leicester, Hodgkin Building, Leicester LE1 9HN, UKDepartment of Biochemistry, University of Leicester, Henry Wellcome Building, Leicester LE1 9HN, UKMRC Toxicology Unit, University of Leicester, Hodgkin Building, Leicester LE1 9HN, UKBAK activation represents a key step during apoptosis, but how it converts into a mitochondria-permeabilizing pore remains unclear. By further delineating the structural rearrangements involved, we reveal that BAK activation progresses through a series of independent steps: BH3-domain exposure, N-terminal change, oligomerization, and membrane insertion. Employing a “BCL-XL-addiction” model, we show that neutralization of BCL-XL by the BH3 mimetic ABT-737 resulted in death only when cells were reconstituted with BCL-XL:BAK, but not BCL-2/ BCL-XL:BIM complexes. Although this resembles the indirect model, release of BAK from BCL-XL did not result in spontaneous adoption of the pore conformation. Commitment to apoptosis required association of the direct activator BIM with oligomeric BAK promoting its conversion to a membrane-inserted pore. The sequential nature of this cascade provides multiple opportunities for other BCL-2 proteins to interfere with or promote BAK activation and unites aspects of the indirect and direct activation models.http://www.sciencedirect.com/science/article/pii/S2211124713005184 |
| spellingShingle | Kathrin Weber Nicholas Harper John Schwabe Gerald M. Cohen BIM-Mediated Membrane Insertion of the BAK Pore Domain Is an Essential Requirement for Apoptosis Cell Reports |
| title | BIM-Mediated Membrane Insertion of the BAK Pore Domain Is an Essential Requirement for Apoptosis |
| title_full | BIM-Mediated Membrane Insertion of the BAK Pore Domain Is an Essential Requirement for Apoptosis |
| title_fullStr | BIM-Mediated Membrane Insertion of the BAK Pore Domain Is an Essential Requirement for Apoptosis |
| title_full_unstemmed | BIM-Mediated Membrane Insertion of the BAK Pore Domain Is an Essential Requirement for Apoptosis |
| title_short | BIM-Mediated Membrane Insertion of the BAK Pore Domain Is an Essential Requirement for Apoptosis |
| title_sort | bim mediated membrane insertion of the bak pore domain is an essential requirement for apoptosis |
| url | http://www.sciencedirect.com/science/article/pii/S2211124713005184 |
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