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

2021 ◽  
Author(s):  
Jordane Preto ◽  
Hubert Gorny ◽  
Isabelle Krimm
Keyword(s):  
Anion Channel ◽  
Voltage Dependent Anion Channel ◽  
Deep Dive ◽  
Accelerated Molecular Dynamics ◽  
Mitochondrial Transporter ◽  
Voltage Dependent ◽  
Key Factor ◽  
Gated Channel ◽  
Conformational Landscape ◽  
Transport Of Ions

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.

scholarly journals Evolutionary selection of a 19-stranded mitochondrial β-barrel scaffold bears structural and functional significance

2020 ◽  
Vol 295 (43) ◽  
pp. 14653-14665
Author(s):  
Shashank Ranjan Srivastava ◽  
Radhakrishnan Mahalakshmi
Keyword(s):  
Functional Significance ◽  
Anion Channel ◽  
Dependent Manner ◽  
Structural Adaptation ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent ◽  
Gated Channel ◽  
Engineered Structures ◽  
Transmembrane Transporters

Transmembrane β-barrels of eukaryotic outer mitochondrial membranes (OMMs) are major channels of communication between the cytosol and mitochondria and are indispensable for cellular homeostasis. A structurally intriguing exception to all known transmembrane β-barrels is the unique odd-stranded, i.e. 19-stranded, structures found solely in the OMM. The molecular origins of this 19-stranded structure and its associated functional significance are unclear. In humans, the most abundant OMM transporter is the voltage-dependent anion channel. Here, using the human voltage-dependent anion channel as our template scaffold, we designed and engineered odd- and even-stranded structures of smaller (V216, V217, V218) and larger (V220, V221) barrel diameters. Determination of the structure, dynamics, and energetics of these engineered structures in bilayer membranes reveals that the 19-stranded barrel surprisingly holds modest to low stability in a lipid-dependent manner. However, we demonstrate that this structurally metastable protein possesses superior voltage-gated channel regulation, efficient mitochondrial targeting, and in vivo cell survival, with lipid-modulated stability, all of which supersede the occurrence of a metastable 19-stranded scaffold. We propose that the unique structural adaptation of these transmembrane transporters exclusively in mitochondria bears strong evolutionary basis and is functionally significant for homeostasis.

scholarly journals The intrinsically disordered N-terminus of the voltage-dependent anion channel

2020 ◽  
Author(s):  
Jordane Preto ◽  
Isabelle Krimm
Keyword(s):  
Anion Channel ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent Anion Channel ◽  
Free Peptide ◽  
Intrinsically Disordered ◽  
Gating Mechanism ◽  
N Terminus ◽  
Intrinsically Disordered Region ◽  
Voltage Dependent ◽  
Transport Of Ions

AbstractThe voltage-dependent anion channel (VDAC) is a critical β-barrel membrane protein of the mitochondrial outer membrane, which regulates the transport of ions and ATP between mitochondria and the cytoplasm. In addition, VDAC plays a central role in the control of apoptosis and is therefore of great interest in both cancer and neurodegenerative diseases. Although not fully understood, it is presumed that the gating mechanism of VDAC is governed by its N-terminal region which, in the open state of the channel, exhibits an α-helical structure positioned midway inside the pore and strongly interacting with the β-barrel wall.In the present work, we performed molecular simulations with a recently developed force field for disordered systems to shed new light on known experimental results, showing that the N-terminus of VDAC is an intrinsically disordered region (IDR). First, simulation of the N-terminal segment as a free peptide highlighted its disordered nature and the importance of using an IDR-specific force field to properly sample its conformational landscape. Secondly, accelerated dynamics simulation of a double cysteine VDAC mutant under applied voltage revealed metastable low conducting states of the channel representative of closed states observed experimentally. Related structures were characterized by partial unfolding and rearrangement of the N-terminal tail, that led to steric hindrance of the pore. Our results indicate that the disordered properties of the N-terminus are crucial to properly account for the gating mechanism of VDAC.Author summaryThe voltage-dependent anion channel (VDAC) is a membrane protein playing a pivotal role in the transport of ions or ATP across the mitochondrial outer membrane as well as in the induction of apoptosis. At high enough membrane potential, VDAC is known to transition from an open state to multiple closed states, reducing the flow of ions through the channel and blocking the passage of large metabolites. While the structure of the open state was resolved more than a decade ago, a molecular description of the gating mechanism of the channel is still missing. Here we show that the N-terminus of VDAC is an intrinsically disordered region and that such a property has a profound impact on its dynamics either as a free peptide or as part of the channel. By taking disordered properties of the N-terminus into account, we managed to generate long-lived closed conformations of the channel at experimental values of the membrane potential. Our results provide new insights into the molecular mechanism driving the gating of VDAC.

scholarly journals VDAC1 in the diseased myocardium and the effect of VDAC1-interacting compound on atrial fibrosis induced by hyperaldosteronism

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hadar Klapper-Goldstein ◽  
Ankit Verma ◽  
Sigal Elyagon ◽  
Roni Gillis ◽  
Michael Murninkas ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Apoptotic Cell ◽  
Anion Channel ◽  
Immunohistochemical Analysis ◽  
Voltage Dependent Anion Channel ◽  
Cardiac Tissues ◽  
Therapeutic Implications ◽  
Voltage Dependent ◽  
Models Of Lupus

AbstractThe voltage-dependent anion channel 1 (VDAC1) is a key player in mitochondrial function. VDAC1 serves as a gatekeeper mediating the fluxes of ions, nucleotides, and other metabolites across the outer mitochondrial membrane, as well as the release of apoptogenic proteins initiating apoptotic cell death. VBIT-4, a VDAC1 oligomerization inhibitor, was recently shown to prevent mitochondrial dysfunction and apoptosis, as validated in mouse models of lupus and type-2 diabetes. In the present study, we explored the expression of VDAC1 in the diseased myocardium of humans and rats. In addition, we evaluated the effect of VBIT-4 treatment on the atrial structural and electrical remodeling of rats exposed to excessive aldosterone levels. Immunohistochemical analysis of commercially available human cardiac tissues revealed marked overexpression of VDAC1 in post-myocardial infarction patients, as well as in patients with chronic ventricular dilatation\dysfunction. In agreement, rats exposed to myocardial infarction or to excessive aldosterone had a marked increase of VDAC1 in both ventricular and atrial tissues. Immunofluorescence staining indicated a punctuated appearance typical for mitochondrial-localized VDAC1. Finally, VBIT-4 treatment attenuated the atrial fibrotic load of rats exposed to excessive aldosterone without a notable effect on the susceptibility to atrial fibrillation episodes induced by burst pacing. Our results indicate that VDAC1 overexpression is associated with myocardial abnormalities in common pathological settings. Our data also indicate that inhibition of the VDAC1 can reduce excessive fibrosis in the atrial myocardium, a finding which may have important therapeutic implications. The exact mechanism\s of this beneficial effect need further studies.

scholarly journals Identification of two voltage-dependent anion channel-like protein sequences conserved in Kinetoplastida

2012 ◽  
Vol 8 (3) ◽  
pp. 446-449 ◽  
Author(s):  
Nadine Flinner ◽  
Enrico Schleiff ◽  
Oliver Mirus
Keyword(s):  
Outer Membrane ◽  
Trypanosoma Brucei ◽  
Protein Sequences ◽  
Anion Channel ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent

The eukaryotic porin superfamily consists of two families, voltage-dependent anion channel (VDAC) and Tom40, which are both located in the mitochondrial outer membrane. In Trypanosoma brucei , only a single member of the VDAC family has been described. We report the detection of two additional eukaryotic porin-like sequences in T. brucei . By bioinformatic means, we classify both as putative VDAC isoforms.

scholarly journals TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

2016 ◽  
Vol 473 (2) ◽  
pp. 107-121 ◽  
Author(s):  
Jemma Gatliff ◽  
Michelangelo Campanella
Keyword(s):  
Neurological Diseases ◽  
Anion Channel ◽  
Translocator Protein ◽  
Endocrine Regulation ◽  
Voltage Dependent Anion Channel ◽  
Steroid Synthesis ◽  
Cellular Processes ◽  
Cellular Events ◽  
Voltage Dependent

The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

Abstract 189: Activation of Voltage-Dependent Anion Channel 2 Suppresses Ca 2+ -Induced Cardiac Arrhythmia

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Jaunian Chen ◽  
Johann Schredelseker ◽  
Hirohito Shimizu ◽  
Jie Huang ◽  
Kui Lu ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Cardiac Arrhythmia ◽  
Critical Role ◽  
Anion Channel ◽  
Cardiac Contraction ◽  
Voltage Dependent Anion Channel ◽  
Rescue Effect ◽  
Cardiac Fibrillation ◽  
Wide Range ◽  
Voltage Dependent

Abnormal Ca2+ handling in cardiac muscle cells is associated with a wide range of human cardiac diseases, including heart failure and cardiac arrhythmias. Zebrafish tremblor (tre) mutant embryos manifest unsynchronized cardiac contractions due to a Ca2+ extrusion defect in cardiomyocytes and thus are used as an animal model for aberrant Ca2+ homeostasis-induced cardiac arrhythmia. To further dissect molecular mechanisms regulating cardiac Ca2+ homeostasis, we conducted a chemical suppressor screen on tre and found that efsevin, a synthetic compound, potently suppresses cardiac fibrillation and restores rhythmic cardiac contractions in tre embryos. In addition, the treatment with efsevin blocks the propagation of arrhythmogenic Ca2+ waves and accelerates the decay phase of Ca2+ sparks in adult murine cardiomyocytes under Ca2+ overload conditions, demonstrating that efsevin modulates Ca2+ handling in both embryonic and adult cardiac tissues. Through a biochemical pulldown assay, we identified a direct interaction between efsevin and VDAC2, a mitochondrial outer membrane voltage dependent anion channel. Overexpression of VDAC2 restores synchronized cardiac contraction in tre and knocking down VDAC2 activity abolishes the rescue effect of efsevin on tre, suggesting that efsevin modulates cardiac Ca2+ homeostasis by potentiating VDAC2 activity. We further showed that enhancing mitochondria Ca2+ uptake by overexpressing MICU or MCU suppresses cardiac fibrillation in tre just like VDAC2 does. Interestingly, this suppressive effect is absent in tre/vdac2 double deficient embryos and co-expression of VDAC2 and MICU or MCU results in synergistic rescue effect on tre, indicating a critical role for mitochondria in regulating cardiac Ca2+ handling and rhythmicity and suggesting that VDAC2 functions as a gate for transporting Ca2+ across the outer membrane. Taken together, our findings identify efsevin as a potent pharmacological tool to modulate cardiac Ca2+ handling, suggest a critical role of mitochondria in the control of cardiac rhythmicity and establish VDAC2 as a modulator of cardiac Ca2+ handling and a potential therapeutic target for the treatment of arrhythmias.

Sign in / Sign up

Export Citation Format

Share Document