A Deep Dive into VDAC1 Conformational Diversity Using All-Atom Simulations Provides New Insights into the Structural Origin of the Closed States
| Autor: | Jordane Preto, Hubert Gorny, Isabelle Krimm |
|---|---|
| Přispěvatelé: | Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Krimm, Isabelle |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Models
Molecular Protein Conformation [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] QH301-705.5 beta-barrel transporter voltage-dependent anion channel [SDV.CAN]Life Sciences [q-bio]/Cancer Molecular Dynamics Simulation Catalysis Inorganic Chemistry Mice [SDV.CAN] Life Sciences [q-bio]/Cancer Animals Physical and Theoretical Chemistry Biology (General) Molecular Biology QD1-999 Spectroscopy [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] Voltage-Dependent Anion Channel 1 Organic Chemistry General Medicine molecular dynamics Computer Science Applications Chemistry Ion Channel Gating |
| Zdroj: | International Journal of Molecular Sciences, Vol 23, Iss 1175, p 1175 (2022) International Journal of Molecular Sciences International Journal of Molecular Sciences, 2022, 23 (3), pp.1175. ⟨10.3390/ijms23031175⟩ International Journal of Molecular Sciences; Volume 23; Issue 3; Pages: 1175 |
| ISSN: | 1661-6596 1422-0067 |
| DOI: | 10.3390/ijms23031175⟩ |
| Popis: | The voltage-dependent anion channel 1 (VDAC1) is a crucial mitochondrial transporter which controls the flow of ions and respiratory metabolites entering or exiting mitochondria. As a voltage-gated channel, VDAC1 can switch between a high conducting “open” state and low conducting “closed” states emerging at high transmembrane potential. Although cell homeostasis depends on channel gating to regulate the transport of ions and metabolites, structural hallmarks characterizing the closed states remain unknown. Here we performed microsecond accelerated molecular dynamics to highlight a vast region of VDAC1 conformational landscape accessible at typical voltage known to promote closure. Conformers exhibiting stable subconducting properties inherent to closed states were identified. In all cases, the low conductance was due to the particular positioning of an unfolded part of the N-terminus which obstructed the channel pore. While the N-terminal tail was found to be sensitive to voltage orientation, our low-conducting models suggest that closed states predominantly take place from disordered events and do not result from the displacement of a voltage sensor or a significant change in the pore. In addition, our results were consistent with conductance jumps observed in experiments and corroborates a recent study describing entropy as a key factor for VDAC gating. |
| Databáze: | OpenAIRE |
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