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.

Biochemie Zentrum Heidelberg University of Heidelberg 69120 Heidelberg Germany

Departament de Bioquímica i Biologia Molecular Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina Universitat de València E 46100 Burjassot Spain

Department of Physics University of Helsinki FI 00014 Helsinki Finland

Laboratorio de Péptidos y Proteínas Centro de Investigación Príncipe Felipe 46012 Valencia Spain

Molecular Modeling Laboratory Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences 166 10 Prague 6 Czech Republic

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