Abstract
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.
Highlights
Voltage Dependent Anion-selective Channels (VDACs) are a small family of conserved proteins mainly located in the outer mitochondrial membrane, whose permeability they guarantee [1,2,3]
In addition to the pore-forming function, VDAC1 is involved in various interactions and cross-talk with other cellular proteins like hexokinase [8], tubulin [9], the Ca2+ gating into mitochondria [10] and the Bcl-2 family members [11] that can impact on the activity of the pore itself and vice versa, testimony to the involvement of VDAC to crucial cell fates [12] like in pathways leading to apoptosis [13,14,15], cancer [16,17] and degeneration [18]
The translocation through a relatively large protein channel such as the VDAC is expected to depend on their mobility in water, the electrostatics of the lumen and the protein dynamics
Summary
Voltage Dependent Anion-selective Channels (VDACs) are a small family of conserved proteins mainly located in the outer mitochondrial membrane, whose permeability they guarantee [1,2,3]. They conduct ions, metabolites and small molecules, among which the energetic nucleotides ATP, ADP and NADH, with limitations due to the physical available size of the channel’s conduit [4]. Three different VDAC isoforms have been characterized in higher eukaryotes, encoded by three separate genes [3,5]. It is not surprising that VDAC1 has been the most extensively characterized isoform. In addition to the pore-forming function, VDAC1 is involved in various interactions and cross-talk with other cellular proteins like hexokinase [8], tubulin [9], the Ca2+ gating into mitochondria [10] and the Bcl-2 family members [11] that can impact on the activity of the pore itself and vice versa, testimony to the involvement of VDAC to crucial cell fates [12] like in pathways leading to apoptosis [13,14,15], cancer [16,17] and degeneration [18]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
