Voltage-Dependent Anion selective Channels (VDAC) are poreforming mitochondrial outer membrane proteins. The three VDAC isoforms show conserved sequences, similar structures and the same gene organization [1]. The meaning of three proteins encoded in different chromosomes must thus be searched for subtle differences at the amino acid level. Among others, cysteine content is noticeable. In humans, VDAC1 has 2, VDAC2 has 9 and VDAC3 has 6 cysteines. VDAC3, the least characterized isoform, presents a set of cysteines predicted to be exposed towards the intermembrane space [2], making them a preferred target for oxidation by ROS. By mass spectrometry we found in VDAC3 a single disulfide bridge and other cysteine oxidated states [3]. Chemico-physical techniques revealed an important function of cysteines in the structural stabilization of the pore. Selective deletion by mutagenesis of VDAC3 cysteines, followed by in vitro conductance experiments and complementation assays in Δporin1 yeast, highlighted their influence on the protein function [3]. This work provides evidence for a complex oxidation pattern of VDAC3, even though it is not directly involved in electron transport.We propose a role of VDAC3 in buffering themitochondria ROS load and in keeping track of the redox level in the intermembrane space, eventually signaling it through conformational changes.

Can modification of VDAC(s) cysteine residues act as a sensor of oxidative state of the intermembrane space of mitochondria?

S. Reina;SALETTI, Rosaria;F. Guarino;A. Magrì;FOTI, Salvatore;MESSINA, Angela Anna;DE PINTO, Vito Nicola
2016

Abstract

Voltage-Dependent Anion selective Channels (VDAC) are poreforming mitochondrial outer membrane proteins. The three VDAC isoforms show conserved sequences, similar structures and the same gene organization [1]. The meaning of three proteins encoded in different chromosomes must thus be searched for subtle differences at the amino acid level. Among others, cysteine content is noticeable. In humans, VDAC1 has 2, VDAC2 has 9 and VDAC3 has 6 cysteines. VDAC3, the least characterized isoform, presents a set of cysteines predicted to be exposed towards the intermembrane space [2], making them a preferred target for oxidation by ROS. By mass spectrometry we found in VDAC3 a single disulfide bridge and other cysteine oxidated states [3]. Chemico-physical techniques revealed an important function of cysteines in the structural stabilization of the pore. Selective deletion by mutagenesis of VDAC3 cysteines, followed by in vitro conductance experiments and complementation assays in Δporin1 yeast, highlighted their influence on the protein function [3]. This work provides evidence for a complex oxidation pattern of VDAC3, even though it is not directly involved in electron transport.We propose a role of VDAC3 in buffering themitochondria ROS load and in keeping track of the redox level in the intermembrane space, eventually signaling it through conformational changes.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/56713
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