Mcl-1 and Bok transmembrane domains : Unexpected players in the modulation of apoptosis
| Autor: | Vicente Andreu-Fernández, Matti Javanainen, Gerard Duart, Ismael Mingarro, Diego Leiva, Mar Orzáez, Fabio Lolicato, Waldemar Kulig, Estefanía Lucendo, Mónica Sancho |
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| Přispěvatelé: | Department of Physics |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Protein family Mitochondrion BCL-X(L) Endoplasmic Reticulum Interactome 114 Physical sciences 03 medical and health sciences Bok 0302 clinical medicine Protein Domains MITOCHONDRIA hemic and lymphatic diseases Animals Humans Bcl-2 Inner mitochondrial membrane Multidisciplinary Cell Death Chemistry Endoplasmic reticulum apoptosis Mcl-1 PATHWAYS LOCALIZATION Biological Sciences Transmembrane protein 3. Good health Cell biology transmembrane Transmembrane domain stomatognathic diseases GLYCOPHORIN-A DIMERIZATION 030104 developmental biology HELIX PACKING Proto-Oncogene Proteins c-bcl-2 BAX 030220 oncology & carcinogenesis Mitochondrial Membranes PROSURVIVAL BCL-2 PROTEINS MOTIF SURVIVAL Myeloid Cell Leukemia Sequence 1 Protein 1182 Biochemistry cell and molecular biology Bacterial outer membrane HeLa Cells |
| Zdroj: | Proc Natl Acad Sci U S A |
| Popis: | The Bcl-2 protein family comprises both proand 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 mem-bers 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. |
| Databáze: | OpenAIRE |
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