title: The N-Terminal Peptides of the Three Human Isoforms of the Mitochondrial Voltage-Dependent Anion Channel Have Different Helical Propensities.
abstract: The voltage-dependent anion channel (VDAC) is the main mitochondrial porin allowing the exchange of ions and metabolites between the cytosol and the mitochondrion. In addition, VDAC was found to actively interact with proteins playing a fundamental role in the regulation of apoptosis and being of central interest in cancer research. VDAC is a large transmembrane β-barrel channel, whose N-terminal helical fragment adheres to the channel interior, partially closing the pore. This fragment is considered to play a key role in protein stability and function as well as in the interaction with apoptosis-related proteins. Three VDAC isoforms are differently expressed in higher eukaryotes, for which distinct and complementary roles are proposed. In this work, the folding propensity of their N-terminal fragments has been compared. By using multiple spectroscopic techniques, and complementing the experimental results with theoretical computer-assisted approaches, we have characterized their conformational equilibrium. Significant differences were found in the intrinsic helical propensity of the three peptides, decreasing in the following order: hVDAC2 > hVDAC3 > hVDAC1. In light of the models proposed in the literature to explain voltage gating, selectivity, and permeability, as well as interactions with functionally related proteins, our results suggest that the different chemicophysical properties of the N-terminal domain are possibly correlated to different functions for the three isoforms. The overall emerging picture is that a similar transmembrane water accessible conduit has been equipped with not identical domains, whose differences can modulate the functional roles of the three VDAC isoforms.
authors: Department of Physics, University of Cagliari , 09042 Monserrato, Italy.
authors: Carlo
authors: C
authors: Guardiani
authors: Department of Biomedical Sciences, Biochemistry Unit, University of Cagliari , 09042 Monserrato, Italy.|Istituto Officina dei Materiali del Consiglio Nazionale delle Ricerche (IOM-CNR), UOS , Cagliari, Italy.
authors: Mariano Andrea
authors: MA
authors: Scorciapino
authors: Department of Chemical and Geological Sciences, University of Cagliari , 09042 Monserrato, Italy.
authors: Giuseppe Federico
authors: GF
authors: Amodeo
authors: National Institute of Chemistry , Ljubljana, Slovenia.
authors: Joze
authors: J
authors: Grdadolnik
authors: CNR Institute of Biostructures and Bioimaging , Catania, Italy.
authors: Giuseppe
authors: G
authors: Pappalardo
authors: Department of Biological, Geological and Environmental Sciences, Section of Molecular Biology, University of Catania, and National Institute for Biostructures and Biosystems, Section of Catania , Catania, Italy.
authors: Vito
authors: V
authors: De Pinto
authors: Department of Physics, University of Cagliari , 09042 Monserrato, Italy.|Istituto Officina dei Materiali del Consiglio Nazionale delle Ricerche (IOM-CNR), UOS , Cagliari, Italy.
authors: Matteo
authors: M
authors: Ceccarelli
authors: Department of Chemical and Geological Sciences, University of Cagliari , 09042 Monserrato, Italy.
authors: Mariano
authors: M
authors: Casu
mesh_terms: D002942:Circular Dichroism; D019295:Computational Biology; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry*; D024101:Mitochondrial Proteins / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry*; D020033:Protein Isoforms / Q000737:chemistry; D017433:Protein Structure, Secondary; D013055:Spectrophotometry, Infrared; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry*; D050996:Voltage-Dependent Anion Channel 2 / Q000737:chemistry*; D050994:Voltage-Dependent Anion Channels / Q000737:chemistry*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D010455:Peptides; D020033:Protein Isoforms; C494762:VDAC1 protein, human; C494765:VDAC2 protein, human; C494768:VDAC3 protein, human; D050996:Voltage-Dependent Anion Channel 2; D050994:Voltage-Dependent Anion Channels; D050995:Voltage-Dependent Anion Channel 1