title: Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.
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.
authors.affiliation: Department of Chemical and Geological Science, University of Cagliari, Cagliari, Italy.
authors.forename: Giuseppe Federico
authors.initials: GF
authors.lastname: Amodeo
authors.affiliation: Department of Physics, University of Cagliari, Cagliari, Italy; Istituto Officina dei Materiali, Consiglio Nazionale delle Ricerche, Cagliari, Italy.
authors.forename: Mariano Andrea
authors.initials: MA
authors.lastname: Scorciapino
authors.affiliation: Department of Biological, Geological and Environmental Sciences, Section of Molecular Biology, University of Catania, Catania, Italy; National Institute for Biomembranes and Biosystems, Catania, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Messina
authors.affiliation: Department of Biological, Geological and Environmental Sciences, Section of Molecular Biology, University of Catania, Catania, Italy; National Institute for Biomembranes and Biosystems, Catania, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: De Pinto
authors.affiliation: Department of Physics, University of Cagliari, Cagliari, Italy; Istituto Officina dei Materiali, Consiglio Nazionale delle Ricerche, Cagliari, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Ceccarelli
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D020033:Protein Isoforms; C494762:VDAC1 protein, human; C494768:VDAC3 protein, human; D050994:Voltage-Dependent Anion Channels; D050995:Voltage-Dependent Anion Channel 1
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