Anti-apoptotic BCL-2 regulation by changes in dynamics of its long unstructured loop
BCL-2, a key protein in inhibiting apoptosis, has a 65-residue-long highly flexible loop domain (FLD) located on the opposite side of its ligand-binding groove. In vivo phosphorylation of the FLD enhances the affinity of BCL-2 for pro-apoptotic ligands, and consequently anti-apoptotic activity. However, it remains unknown as to how the faraway, unstructured FLD modulates the affinity. Here we investigate the protein-ligand interactions by fluorescence techniques and monitor protein dynamics by DEER and NMR spectroscopy tools. We show that phosphomimetic mutations on the FLD lead to a reduction in structural flexibility, hence promoting ligand access to the groove. The bound pro-apoptotic ligands can be displaced by the BCL-2-selective inhibitor ABT-199 efficiently, and thus released to trigger apoptosis. We show that changes in structural flexibility on an unstructured loop can activate an allosteric protein that is otherwise structurally inactive.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:3 |
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| Enthalten in: |
Communications biology - 3(2020), 1 vom: 12. Nov., Seite 668 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lan, Yu-Jing [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.06.2021 Date Revised 30.03.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s42003-020-01390-6 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM317519018 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BCL-2, a key protein in inhibiting apoptosis, has a 65-residue-long highly flexible loop domain (FLD) located on the opposite side of its ligand-binding groove. In vivo phosphorylation of the FLD enhances the affinity of BCL-2 for pro-apoptotic ligands, and consequently anti-apoptotic activity. However, it remains unknown as to how the faraway, unstructured FLD modulates the affinity. Here we investigate the protein-ligand interactions by fluorescence techniques and monitor protein dynamics by DEER and NMR spectroscopy tools. We show that phosphomimetic mutations on the FLD lead to a reduction in structural flexibility, hence promoting ligand access to the groove. The bound pro-apoptotic ligands can be displaced by the BCL-2-selective inhibitor ABT-199 efficiently, and thus released to trigger apoptosis. We show that changes in structural flexibility on an unstructured loop can activate an allosteric protein that is otherwise structurally inactive | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a BCL2 protein, human |2 NLM | |
| 650 | 7 | |a Bridged Bicyclo Compounds, Heterocyclic |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-bcl-2 |2 NLM | |
| 650 | 7 | |a Recombinant Proteins |2 NLM | |
| 650 | 7 | |a Sulfonamides |2 NLM | |
| 650 | 7 | |a venetoclax |2 NLM | |
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| 700 | 1 | |a Yeh, Pei-Shan |e verfasserin |4 aut | |
| 700 | 1 | |a Kao, Te-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Lo, Yuan-Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Sue, Shih-Che |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yu-Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Hwang, Dennis W |e verfasserin |4 aut | |
| 700 | 1 | |a Chiang, Yun-Wei |e verfasserin |4 aut | |
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