Mcl-1 and Bok transmembrane domains: unexpected players in the modulation of apoptosis
The Bcl-2 protein family comprises both pro- and antiapoptotic members that control the permeabilization of the mitochondrial outer membrane, a crucial step in the modulation of apoptosis. Recent research has demonstrated that the carboxyl-terminal transmembrane domain (TMD) of some Bcl-2 protein fa...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
October 22, 2020
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| In: |
Proceedings of the National Academy of Sciences of the United States of America
Year: 2020, Volume: 117, Issue: 45, Pages: 27980-27988 |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.2008885117 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1073/pnas.2008885117 Verlag, lizenzpflichtig, Volltext: https://www.pnas.org/content/117/45/27980 
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| Author Notes: | Estefanía Lucendo, Mónica Sancho, Fabio Lolicato, Matti Javanainen, Waldemar Kulig, Diego Leiva, Gerard Duart, Vicente Andreu-Fernández, Ismael Mingarro, and Mar Orzáez |
| Summary: | The Bcl-2 protein family comprises both pro- and antiapoptotic members that control the permeabilization of the mitochondrial outer membrane, a crucial step in the modulation of apoptosis. Recent research has demonstrated that the carboxyl-terminal transmembrane domain (TMD) of some Bcl-2 protein family members can modulate apoptosis; however, the transmembrane interactome of the antiapoptotic protein Mcl-1 remains largely unexplored. Here, we demonstrate that the Mcl-1 TMD forms homooligomers in the mitochondrial membrane, competes with full-length Mcl-1 protein with regards to its antiapoptotic function, and induces cell death in a Bok-dependent manner. While the Bok TMD oligomers locate preferentially to the endoplasmic reticulum (ER), heterooligomerization between the TMDs of Mcl-1 and Bok predominantly takes place at the mitochondrial membrane. Strikingly, the coexpression of Mcl-1 and Bok TMDs produces an increase in ER mitochondrial-associated membranes, suggesting an active role of Mcl-1 in the induced mitochondrial targeting of Bok. Finally, the introduction of Mcl-1 TMD somatic mutations detected in cancer patients alters the TMD interaction pattern to provide the Mcl-1 protein with enhanced antiapoptotic activity, thereby highlighting the clinical relevance of Mcl-1 TMD interactions. |
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| Item Description: | Gesehen am 20.01.2021 |
| Physical Description: | Online Resource |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.2008885117 |