Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2
Tumor initiation, progression and resistance to chemotherapy rely on cancer cells bypassing programmed cell death by apoptosis. We report that unlike other pro-apoptotic proteins, Bim contains two distinct binding sites for the anti-apoptotic proteins Bcl-XL and Bcl-2. These include the BH3 sequence...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-03-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/37689 |
| _version_ | 1818026906600079360 |
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| author | Qian Liu Elizabeth J Osterlund Xiaoke Chi Justin Pogmore Brian Leber David William Andrews |
| author_facet | Qian Liu Elizabeth J Osterlund Xiaoke Chi Justin Pogmore Brian Leber David William Andrews |
| author_sort | Qian Liu |
| collection | DOAJ |
| description | Tumor initiation, progression and resistance to chemotherapy rely on cancer cells bypassing programmed cell death by apoptosis. We report that unlike other pro-apoptotic proteins, Bim contains two distinct binding sites for the anti-apoptotic proteins Bcl-XL and Bcl-2. These include the BH3 sequence shared with other pro-apoptotic proteins and an unexpected sequence located near the Bim carboxyl-terminus (residues 181–192). Using automated Fluorescence Lifetime Imaging Microscopy - Fluorescence Resonance Energy Transfer (FLIM-FRET) we show that the two binding interfaces enable Bim to double-bolt lock Bcl-XL and Bcl-2 in complexes resistant to displacement by BH3-mimetic drugs currently in use or being evaluated for cancer therapy. Quantifying in live cells the contributions of individual amino acids revealed that residue L185 previously thought involved in binding Bim to membranes, instead contributes to binding to anti-apoptotic proteins. This double-bolt lock mechanism has profound implications for the utility of BH3-mimetics as drugs. |
| first_indexed | 2024-12-10T04:39:27Z |
| format | Article |
| id | doaj.art-35be500a47c444d396b9241785a6b15f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:39:27Z |
| publishDate | 2019-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-35be500a47c444d396b9241785a6b15f2022-12-22T02:01:55ZengeLife Sciences Publications LtdeLife2050-084X2019-03-01810.7554/eLife.37689Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2Qian Liu0Elizabeth J Osterlund1Xiaoke Chi2https://orcid.org/0000-0002-5269-8389Justin Pogmore3Brian Leber4David William Andrews5https://orcid.org/0000-0002-9266-7157Biological Sciences, Sunnybrook Research Institute, Toronto, CanadaBiological Sciences, Sunnybrook Research Institute, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, CanadaDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, CanadaDepartment of Biochemistry, University of Toronto, Toronto, CanadaDepartment of Medicine, McMaster University, Hamilton, CanadaDepartment of Biochemistry, University of Toronto, Toronto, CanadaTumor initiation, progression and resistance to chemotherapy rely on cancer cells bypassing programmed cell death by apoptosis. We report that unlike other pro-apoptotic proteins, Bim contains two distinct binding sites for the anti-apoptotic proteins Bcl-XL and Bcl-2. These include the BH3 sequence shared with other pro-apoptotic proteins and an unexpected sequence located near the Bim carboxyl-terminus (residues 181–192). Using automated Fluorescence Lifetime Imaging Microscopy - Fluorescence Resonance Energy Transfer (FLIM-FRET) we show that the two binding interfaces enable Bim to double-bolt lock Bcl-XL and Bcl-2 in complexes resistant to displacement by BH3-mimetic drugs currently in use or being evaluated for cancer therapy. Quantifying in live cells the contributions of individual amino acids revealed that residue L185 previously thought involved in binding Bim to membranes, instead contributes to binding to anti-apoptotic proteins. This double-bolt lock mechanism has profound implications for the utility of BH3-mimetics as drugs. https://elifesciences.org/articles/37689Bcl-2 family proteinsapoptosisBH3-mimetic drugstissue culture cellsfluorescence lifetime imagingForster resonance energy transfer |
| spellingShingle | Qian Liu Elizabeth J Osterlund Xiaoke Chi Justin Pogmore Brian Leber David William Andrews Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2 eLife Bcl-2 family proteins apoptosis BH3-mimetic drugs tissue culture cells fluorescence lifetime imaging Forster resonance energy transfer |
| title | Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2 |
| title_full | Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2 |
| title_fullStr | Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2 |
| title_full_unstemmed | Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2 |
| title_short | Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2 |
| title_sort | bim escapes displacement by bh3 mimetic anti cancer drugs by double bolt locking both bcl xl and bcl 2 |
| topic | Bcl-2 family proteins apoptosis BH3-mimetic drugs tissue culture cells fluorescence lifetime imaging Forster resonance energy transfer |
| url | https://elifesciences.org/articles/37689 |
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