Concentration Dependent Ion Selectivity in VDAC: A Molecular Dynamics Simulation Study

Krammer, Eva-Maria; Homblé, Fabrice; Prévost, Martine

doi:10.1371/journal.pone.0027994

Cited by 29 publications

(56 citation statements)

References 83 publications

(140 reference statements)

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“…This is in agreement with [50], where ion-pairing was investigated in detail, and provides a valid explanation for the high positive correlation we found between the time averaged number of Cl − and K + in the lumen (table 2). …”

Section: Resultssupporting

confidence: 92%

Charged Residues Distribution Modulates Selectivity of the Open State of Human Isoforms of the Voltage Dependent Anion-Selective Channel

et al. 2014

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Voltage Dependent Anion-selective Channels (VDACs) are pore-forming proteins located in the outer mitochondrial membrane. They are responsible for the access of ions and energetic metabolites into the inner membrane transport systems. Three VDAC isoforms exist in mammalian, but their specific role is unknown. In this work we have performed extensive (overall ∼5 µs) Molecular Dynamics (MD) simulations of the human VDAC isoforms to detect structural and conformational variations among them, possibly related to specific functional roles of these proteins. Secondary structure analysis of the N-terminal domain shows a high similarity among the three human isoforms of VDAC but with a different plasticity. In particular, the N-terminal domain of the hVDAC1 is characterized by a higher plasticity, with a ∼20% occurrence for the ‘unstructured’ conformation throughout the folded segment, while hVDAC2, containing a peculiar extension of 11 amino acids at the N-terminal end, presents an additional 310-helical folded portion comprising residues 10′ to 3, adhering to the barrel wall. The N-terminal sequences of hVDAC isoforms are predicted to have a low flexibility, with possible consequences in the dynamics of the human VDACs. Clear differences were found between hVDAC1 and hVDAC3 against hVDAC2: a significantly modified dynamics with possible important consequence on the voltage-gating mechanism. Charge distribution inside and at the mouth of the pore is responsible for a different preferential localization of ions with opposite charge and provide a valuable rationale for hVDAC1 and hVDAC3 having a Cl−/K+ selectivity ratio of 1.8, whereas hVDAC2 of 1.4. Our conclusion is that hVDAC isoforms, despite sharing a similar scaffold, have modified working features and a biological work is now requested to give evidence to the described dissimilarities.

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Section: Resultssupporting

confidence: 92%

Charged Residues Distribution Modulates Selectivity of the Open State of Human Isoforms of the Voltage Dependent Anion-Selective Channel

et al. 2014

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“…Under our BLM conditions, reconstituted mVDAC1 exhibited a 3.94±0.04 nS conductance in the open state (S0), consistent with previous observations, whereas the average conductance of the closed state was 2.34±0.06 nS, differing significantly from previously published values (Table 1) [3], [27], [39], [40], [41], [47]. Instead the closed state of mVDAC1 shows a broad distribution between two already previously recognized but not defined major states (S1, S2) [48].…”

Section: Discussionsupporting

confidence: 91%

Flexibility of the N-Terminal mVDAC1 Segment Controls the Channel’s Gating Behavior

et al. 2012

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Since the solution of the molecular structures of members of the voltage dependent anion channels (VDACs), the N-terminal α-helix has been the main focus of attention, since its strategic location, in combination with its putative conformational flexibility, could define or control the channel’s gating characteristics. Through engineering of two double-cysteine mVDAC1 variants we achieved fixing of the N-terminal segment at the bottom and midpoint of the pore. Whilst cross-linking at the midpoint resulted in the channel remaining constitutively open, cross-linking at the base resulted in an “asymmetric” gating behavior, with closure only at one electric field´s orientation depending on the channel’s orientation in the lipid bilayer. Additionally, and while the native channel adopts several well-defined closed states (S1 and S2), the cross-linked variants showed upon closure a clear preference for the S2 state. With native-channel characteristics restored following reduction of the cysteines, it is evident that the conformational flexibility of the N-terminal segment plays indeed a major part in the control of the channel’s gating behavior.

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“…However, it is not clear how closely Table 1) and the membranes used lack proteins and sterols. Similarly, molecular dynamics simulations use single lipids such as DMPC [21], [17], [56]) or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE, [78]). …”

Section: Accepted Manuscriptmentioning

confidence: 99%

The N-terminus of VDAC: Structure, mutational analysis, and a potential role in regulating barrel shape

Shuvo

Ferens

Court

2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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A novel feature of the voltage-dependent anion channel (VDAC, mitochondrial porin), is the barrel, comprising an odd number of β-strands and closed by parallel strands. Recent research has focused on the N-terminal segment, which in the available structures, resides in the lumen and is not part of the barrel. In this review, the structural data obtained from vertebrate VDAC are integrated with those from VDAC in artificial bilayers, emphasizing the array of native and tagged versions of VDAC used. The data are discussed with respect to a recent gating model (Zachariae et al. (2012) Structure 20:1-10), in which the N-terminus acts not as a gate on a stable barrel, but rather stabilizes the barrel, preventing its shift into a partially collapsed, low-conductance, closed state. Additionally, the role of the N-terminus in VDAC oligomerization, apoptosis through interactions with hexokinase and its interaction with ATP are discussed briefly.

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Concentration Dependent Ion Selectivity in VDAC: A Molecular Dynamics Simulation Study

Cited by 29 publications

References 83 publications

Charged Residues Distribution Modulates Selectivity of the Open State of Human Isoforms of the Voltage Dependent Anion-Selective Channel

Charged Residues Distribution Modulates Selectivity of the Open State of Human Isoforms of the Voltage Dependent Anion-Selective Channel

Flexibility of the N-Terminal mVDAC1 Segment Controls the Channel’s Gating Behavior

The N-terminus of VDAC: Structure, mutational analysis, and a potential role in regulating barrel shape

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