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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...

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Autores principales: Liu, Qian, Osterlund, Elizabeth J, Chi, Xiaoke, Pogmore, Justin, Leber, Brian, Andrews, David William
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414199/
https://www.ncbi.nlm.nih.gov/pubmed/30860026
http://dx.doi.org/10.7554/eLife.37689
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author Liu, Qian
Osterlund, Elizabeth J
Chi, Xiaoke
Pogmore, Justin
Leber, Brian
Andrews, David William
author_facet Liu, Qian
Osterlund, Elizabeth J
Chi, Xiaoke
Pogmore, Justin
Leber, Brian
Andrews, David William
author_sort Liu, Qian
collection PubMed
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. ​
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spelling pubmed-64141992019-03-14 Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2 Liu, Qian Osterlund, Elizabeth J Chi, Xiaoke Pogmore, Justin Leber, Brian Andrews, David William eLife Cancer Biology 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. ​ eLife Sciences Publications, Ltd 2019-03-12 /pmc/articles/PMC6414199/ /pubmed/30860026 http://dx.doi.org/10.7554/eLife.37689 Text en © 2019, Liu et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Liu, Qian
Osterlund, Elizabeth J
Chi, Xiaoke
Pogmore, Justin
Leber, Brian
Andrews, David William
Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2
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 Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414199/
https://www.ncbi.nlm.nih.gov/pubmed/30860026
http://dx.doi.org/10.7554/eLife.37689
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