High‐resolution analysis of the conformational transition of pro‐apoptotic Bak at the lipid membrane
| العنوان: | High‐resolution analysis of the conformational transition of pro‐apoptotic Bak at the lipid membrane |
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| المؤلفون: | Franz Hagn, Martin Haslbeck, Laura E. Sperl, Florian Rührnößl, Anita Schiller |
| المصدر: | EMBO J.:e107159 (2021) The EMBO Journal EMBO J |
| بيانات النشر: | EMBO, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Models, Molecular, Protein Conformation, alpha-Helical, Protein Folding, Gene Expression, Structural Biology, News & Views, Cloning, Molecular, Lipid bilayer, membrane, Transition (genetics), General Neuroscience, apoptosis, Articles, Recombinant Proteins, ddc, Transmembrane domain, HDX‐MS, bcl-2 Homologous Antagonist-Killer Protein, Membrane, Proto-Oncogene Proteins c-bcl-2, Thermodynamics, Protein folding, Autophagy & Cell Death, biological phenomena, cell phenomena, and immunity, Protein Binding, Apoptosis, Hdx-ms, Lipid Nanodiscs, Nmr, Genetic Vectors, bcl-X Protein, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Membrane Lipids, Escherichia coli, Humans, Protein Interaction Domains and Motifs, Nuclear Magnetic Resonance, Biomolecular, Molecular Biology, lipid nanodiscs, Binding Sites, General Immunology and Microbiology, Mutagenesis, Deuterium Exchange Measurement, Membranes & Trafficking, NMR, Kinetics, Liposomes, Biophysics, Protein Conformation, beta-Strand, Hydrogen–deuterium exchange, Protein Multimerization |
| الوصف: | Permeabilization of the outer mitochondrial membrane by pore‐forming Bcl2 proteins is a crucial step for the induction of apoptosis. Despite a large set of data suggesting global conformational changes within pro‐apoptotic Bak during pore formation, high‐resolution structural details in a membrane environment remain sparse. Here, we used NMR and HDX‐MS (Hydrogen deuterium exchange mass spectrometry) in lipid nanodiscs to gain important high‐resolution structural insights into the conformational changes of Bak at the membrane that are dependent on a direct activation by BH3‐only proteins. Furthermore, we determined the first high‐resolution structure of the Bak transmembrane helix. Upon activation, α‐helix 1 in the soluble domain of Bak dissociates from the protein and adopts an unfolded and dynamic potentially membrane‐bound state. In line with this finding, comparative protein folding experiments with Bak and anti‐apoptotic BclxL suggest that α‐helix 1 in Bak is a metastable structural element contributing to its pro‐apoptotic features. Consequently, mutagenesis experiments aimed at stabilizing α‐helix 1 yielded Bak variants with delayed pore‐forming activity. These insights will contribute to a better mechanistic understanding of Bak‐mediated membrane permeabilization. Outer mitochondrial membrane permeabilization by pore‐forming Bcl2 proteins, including Bak, is crucial for apoptosis. Here, a high‐resolution structural characterization reveals large conformational changes of Bak during activation at the membrane surface. |
| وصف الملف: | application/pdf |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6f6f8639e73210e7b0f39683cc1bf680Test https://mediatum.ub.tum.de/doc/1654755/document.pdfTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6f6f8639e73210e7b0f39683cc1bf680 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |