Mcl-1 and Bok transmembrane domains

• Verfasst von: Lucendo, Estefanía [VerfasserIn]
• Verfasst von: Lolicato, Fabio [VerfasserIn]
• Titel: Mcl-1 and Bok transmembrane domains
• Titelzusatz: unexpected players in the modulation of apoptosis
• Verf.angabe: Estefanía Lucendo, Mónica Sancho, Fabio Lolicato, Matti Javanainen, Waldemar Kulig, Diego Leiva, Gerard Duart, Vicente Andreu-Fernández, Ismael Mingarro, and Mar Orzáez
• E-Jahr: 2020
• Jahr: October 22, 2020
• Umfang: 9 S.
• Fussnoten: Gesehen am 20.01.2021
• Titel Quelle: Enthalten in: National Academy of Sciences (Washington, DC)Proceedings of the National Academy of Sciences of the United States of America
• Ort Quelle: Washington, DC : National Acad. of Sciences, 1915
• Jahr Quelle: 2020
• Band/Heft Quelle: 117(2020), 45, Seite 27980-27988
• ISSN Quelle: 1091-6490
• DOI: doi:10.1073/pnas.2008885117
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: apoptosis
• Sach-SW: Bcl-2
• Sach-SW: Bok
• Sach-SW: Mcl-1
• Sach-SW: transmembrane
• K10plus-PPN: 1745034145

Abstract

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.