Structure, gating and interactions of the voltage-dependent anion channel

Abstract

The voltage-dependent anion channel (VDAC) is one of the most highly abundant proteins found in the outer mitochondrial membrane, and was one of the earliest discovered. Here we review progress in understanding VDAC function with a focus on its structure, discussing various models proposed for voltage gating as well as potential drug targets to modulate the channel’s function. In addition, we explore the sensitivity of VDAC structure to variations in the membrane environment, comparing DMPC-only, DMPC with cholesterol, and near-native lipid compositions, and use magic-angle spinning NMR spectroscopy to locate cholesterol on the outside of the β-barrel. We find that the VDAC protein structure remains unchanged in different membrane compositions, including conditions with cholesterol.

Towards a native environment: structure and function of membrane proteins in lipid bilayers by NMR

“…Both water and lipid correlations were measured for VDAC and AIkL. In addition to lipids/water, cholesterol was recently located on the outside of the beta barrel 93 . From fitting the buildup of protein-lipid/water cross peak intensity, characteristic cross-relaxation times in the range of seconds were measured.…”

“…In addition to lipids/water, cholesterol was recently located on the outside of the beta barrel. 93 From fitting the buildup of protein–lipid/water cross peak intensity, characteristic cross-relaxation times in the range of seconds were measured. These rates also indicate that transfer to lipids must be considered when determining protein mobility from proton T 1 times.…”

The Ionic Selectivity of Lysenin Channels in Open and Sub-Conducting States

“…These features, identified for fully-open lysenin channels, resemble the selectivity of ion channels. However, ion channels such as VDAC [27][28][29][30], mechano-sensitive, [31][32][33], sodium [34], and potassium [35,36] may undergo conformational transitions that lead to intermediate, sub-conducting states. Although the physiological relevance of sub-conductance is poorly understood, adjustments of the ionic permeabilities in such sub-conducting states have been reported [27][28][29].…”

“…However, ion channels such as VDAC [27][28][29][30], mechano-sensitive, [31][32][33], sodium [34], and potassium [35,36] may undergo conformational transitions that lead to intermediate, sub-conducting states. Although the physiological relevance of sub-conductance is poorly understood, adjustments of the ionic permeabilities in such sub-conducting states have been reported [27][28][29]. For a better understanding of how intermediate conductance states adjust the transport properties of protein pores, we exploited a unique feature of lysenin channels, which is the attainment of stable sub-conducting states in the presence of divalent ions (i.e., Ca 2+ ) [12,14].…”

A deep dive into VDAC1 conformational diversity using all-atom simulations provides new insights into the structural origin of the closed states

“…In normal physiological conditions, VDAC1 is stable in its open state. However, lowering the pH [16] or setting the transmembrane (TM) potential below or above a certain threshold value (below −30mV and above +30mV, typically) contributes to the emergence of closed states which are usually shortlived over experimental timescales [17]. Finally, VDAC1 open state was reported to be essentially anion selective displaying a 2:1 Cl - :K + permeability ratio upon a 0.1-1M KCl concentration gradient while closed states showed a preference for cations [15].…”