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.
Highlights
Academic Editor: Alexande BaykovIt is widely accepted that mitochondria are more than the energy powerhouse of the cell given their importance in cell signaling events, aging, cell proliferation and apoptosis [1,2]
Mitochondrion’s cross-talk with the rest of the cell is directly sustained by the voltage-dependent anion channel 1 (VDAC1)—a β-barrel membrane protein located within the mitochondrial outer membrane (MOM) [3], which regulates the transport of ions [4,5] and metabolites (ATP, NADH . . . ) diffusing in or out of mitochondria [6,7]
We found that the only structures exhibiting a relatively stable low conductance compatible with closed states were characterized by a specific positioning of the unstructured N-terminal tail, which partially occluded the pore
Summary
Academic Editor: Alexande BaykovIt is widely accepted that mitochondria are more than the energy powerhouse of the cell given their importance in cell signaling events, aging, cell proliferation and apoptosis [1,2]. VDAC1 plays a central role in many cellular processes ranging from energy metabolism to the triggering of mitochondria-mediated apoptosis [8,9]. For these reasons, VDAC1 is often regarded as a promising target for the treatment of metabolic disorders [10] as well as cancer [11,12] and neurogenerative diseases [13,14] where pro- and anti-apoptotic action are required, respectively. The open state of VDAC1 was reported to be essentially anion-selective, displaying a 2:1 Cl− :K+
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