6533b822fe1ef96bd127d888
RESEARCH PRODUCT
Mcl-1 and Bok transmembrane domains : Unexpected players in the modulation of apoptosis
Vicente Andreu-fernándezMatti JavanainenGerard DuartIsmael MingarroDiego LeivaMar OrzáezFabio LolicatoFabio LolicatoWaldemar KuligEstefanía LucendoMónica Sanchosubject
0301 basic medicineProtein familyMitochondrionBCL-X(L)Endoplasmic ReticulumInteractome114 Physical sciences03 medical and health sciencesBok0302 clinical medicineProtein DomainsMITOCHONDRIAhemic and lymphatic diseasesAnimalsHumansBcl-2Inner mitochondrial membraneMultidisciplinaryCell DeathChemistryEndoplasmic reticulumapoptosisMcl-1PATHWAYSLOCALIZATIONBiological SciencesTransmembrane protein3. Good healthCell biologytransmembraneTransmembrane domainstomatognathic diseasesGLYCOPHORIN-A DIMERIZATION030104 developmental biologyHELIX PACKINGProto-Oncogene Proteins c-bcl-2BAX030220 oncology & carcinogenesisMitochondrial MembranesPROSURVIVAL BCL-2 PROTEINSMOTIFSURVIVALMyeloid Cell Leukemia Sequence 1 Protein1182 Biochemistry cell and molecular biologyBacterial outer membraneHeLa Cellsdescription
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. Peer reviewed
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-10-22 |