A gating mechanism of the BsYetJ calcium channel revealed in an endoplasmic reticulum lipid environment |
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| Institution: | 1. Section on Molecular Transport, Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, United States of America;2. Section on Integrative Biophysics, Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, United States of America;3. Institute for Soft Matter Synthesis and Metrology, Department of Physics, Georgetown University, Washington, DC 20057, United States of America;1. CEFITEC, Department of Physics, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal;2. Laboratory of Instrumentation, Biomedical Engineering and Radiation Physics (LIBPhys-UNL), Department of Physics, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal;3. São Carlos Institute of Physics, University of São Paulo, São Carlos, Brazil;1. Institute of Nutritional and Food Sciences, Molecular Food Technology, University of Bonn, Friedrich-Hirzebruch-Allee 7, D-53115 Bonn, Germany;2. Institute of Nutritional and Food Sciences, Food Microbiology and Hygiene, University of Bonn, Friedrich-Hirzebruch-Allee 7, D-53115 Bonn, Germany;1. Division for Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia;2. Division for Physical Chemistry, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia;3. Department of Mathematics, University of Chemistry and Technology, 166 28 Prague, Czech Republic;1. Departamento de Química, Facultad de Ciencias Exactas, Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas (INIFTA), Universidad Nacional de La Plata (UNLP), CCT La Plata-CONICET, La Plata, Argentina;2. Department of Chemistry, Quebec Center for Advanced Materials (QCAM), McGill University, 801 Sherbrooke Street West, Montreal H3A 0B8, QC, Canada;3. CIHIDECAR-CONICET, Departamento de Química Orgánica, FCEyN, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina |
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| Abstract: | The transmembrane BAX inhibitor-1-containing motif 6 (TMBIM6) is suggested to modulate apoptosis by regulating calcium homeostasis in the endoplasmic reticulum (ER). However, the precise molecular mechanism underlying this calcium regulation remains poorly understood. To shed light on this issue, we investigated all negatively charged residues in BsYetJ, a bacterial homolog of TMBIM6, using mutagenesis and fluorescence-based functional assays. We reconstituted BsYetJ in membrane vesicles with a lipid composition similar to that of the ER. Our results show that the charged residues E49 and R205 work together as a major gate, regulating calcium conductance in these ER-like lipid vesicles. However, these residues become largely inactive when reconstituted in other lipid environments. In addition, we found that D195 acts as a minor filter compared to the E49-R205 dyad. Our study uncovers a previously unknown function of BsYetJ/TMBIM6 in the calcium-dependent inactivation of BsYetJ, providing a framework for the development of a lipid-dependent mechanistic model of BsYetJ that will facilitate our understanding of calcium-dependent apoptosis. |
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