Mcl-1 and Bok transmembrane domains: Unexpected players in the modulation of apoptosis

0535216 - ÚOCHB 2021 RIV US eng J - Journal Article
Lucendo, E. - Sancho, M. - Lolicato, F. - Javanainen, Matti - Kulig, W. - Leiva, D. - Duart, G. - Andreu-Fernández, V. - Mingarro, I. - Orzáez, M.
Mcl-1 and Bok transmembrane domains: Unexpected players in the modulation of apoptosis.
Proceedings of the National Academy of Sciences of the United States of America. Roč. 117, č. 45 (2020), s. 27980-27988. ISSN 0027-8424. E-ISSN 1091-6490
Institutional support: RVO:61388963
Keywords : apoptosis * Bcl-2 * Bok * Mcl-1 * transmembrane
OECD category: Physical chemistry
Impact factor: 11.205, year: 2020
Method of publishing: Limited access
https://doi.org/10.1073/pnas.2008885117

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.
Permanent Link: http://hdl.handle.net/11104/0313479


Research data: Zenodo