A Deep Dive into VDAC1 Conformational Diversity Using All-Atom Simulations Provides New Insights into the Structural Origin of the Closed States - Centre de recherche en cancérologie de Lyon (UMR INSERM 1052 ; CNRS 5286 ; Centre Léon Bérard) Access content directly
Journal Articles International Journal of Molecular Sciences Year : 2022

A Deep Dive into VDAC1 Conformational Diversity Using All-Atom Simulations Provides New Insights into the Structural Origin of the Closed States

Abstract

The voltage-dependent anion channel 1 (VDAC1) is a crucial mitochondrial transporter that 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 a low-conducting “closed” state emerging at high transmembrane (TM) potentials. 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 voltages known to promote closure. Conformers exhibiting durable 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 models suggest that stable low-conducting states of VDAC1 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 experimentally and corroborated a recent study describing entropy as a key factor for VDAC gating.
Fichier principal
Vignette du fichier
VDAC_publi2.pdf (3.16 Mo) Télécharger le fichier
Origin : Publisher files allowed on an open archive

Dates and versions

hal-03856956 , version 1 (17-11-2022)

Identifiers

Cite

Jordane Preto, Hubert Gorny, Isabelle Krimm. A Deep Dive into VDAC1 Conformational Diversity Using All-Atom Simulations Provides New Insights into the Structural Origin of the Closed States. International Journal of Molecular Sciences, 2022, 23 (3), pp.1175. ⟨10.3390/ijms23031175⟩. ⟨hal-03856956⟩
39 View
10 Download

Altmetric

Share

Gmail Facebook X LinkedIn More