On 2014 Oct 03, Friedrich Thinnes commented:

To finalize three-dimensional VDAC structure: Focus on Native VDAC will be indispensable

This study, from my point of view, marks a great moment of VDAC research:

1) It points another time to the relevance of cell membrane-standing VDAC-1 for the pathogenesis of Alzheimer´s Disease via apoptosis.

2) It gives strong support to the cell membrane-expression, more precisely plasmalemmal lipid raft-integration of vertebrate VDAC-1. Furthermore, the data concerning the posphorylation of VDAC-1 in correlation to regulation of channel opening/closing argue in favor of its involvement in cell volume regulation and thus apoptosis. They are in line with much evidence indicating that plasmalemmal VDAC-1 forms the channel part of a volume regulated anion channel complex (VRAC/VSOAC).

3) From here, VDAC-1 in the plasmalemma must be “fully closed” = collapsed = N-terminus accessible outside the barrel = closed for anions and cations, and there is evidence that the N-terminal part of native VDAC-1 can be reached by antibodies even in detergent solutions (Benz et al., 1992; Thinnes and Burckhardt, 2012).

4) Applying canonical incorporation into black membranes, detergent-solubilized native phosphorylated mammalian VDAC-1 as well as recombinant channel preparations from E. coli inclusion bodies show only “open” = anion-selective = N-terminal stretch inside the barrel and “closed” = cation-selective = semi-collapsed = N-terminal stretch inside the barrel channel phenotypes (Teijido et al., 2012). “Fully closed” = collapsed = N-terminus accessible outside the barrel VDAC-1 states thus cannot be studied by this approach. The same holds true for more recent crystallization-based approaches. However, upcoming laser-based approaches may work just on native VDAC-1 in solutions; thus improvements to get detergent solubilized native VDAC preparation may pay to keep on the schedule.

--Benz R, Maier E, Thinnes FP, Götz H, Hilschmann N (1992) Studies on human porin. VII. The channel properties of the human B-lymphocyte membrane-derived “Porin 31HL” are similar to those of mitochondrial porins, Biol. Chem. Hoppe Seyler. 373: 295–303. --Thinnes FP, Burckhardt G (2012) On a fully closed state of native human type-1 VDAC enriched in Nonidet P40. Mol Genet Metab 107: 632-633. --Teijido O, Ujwal R, Hillerdal CO, Kullman L, Rostovtseva TK, Abramson J (2012) Affixing N-terminal α-helix to the wall of the voltage-dependent anion channel does not prevent its voltage gating. J Biol Chem 287: 11437-11445.

On 2014 Oct 03, Friedrich Thinnes commented:

To finalize three-dimensional VDAC structure: Focus on Native VDAC will be indispensable

This study, from my point of view, marks a great moment of VDAC research:

1) It points another time to the relevance of cell membrane-standing VDAC-1 for the pathogenesis of Alzheimer´s Disease via apoptosis.

2) It gives strong support to the cell membrane-expression, more precisely plasmalemmal lipid raft-integration of vertebrate VDAC-1. Furthermore, the data concerning the posphorylation of VDAC-1 in correlation to regulation of channel opening/closing argue in favor of its involvement in cell volume regulation and thus apoptosis. They are in line with much evidence indicating that plasmalemmal VDAC-1 forms the channel part of a volume regulated anion channel complex (VRAC/VSOAC).

3) From here, VDAC-1 in the plasmalemma must be “fully closed” = collapsed = N-terminus accessible outside the barrel = closed for anions and cations, and there is evidence that the N-terminal part of native VDAC-1 can be reached by antibodies even in detergent solutions (Benz et al., 1992; Thinnes and Burckhardt, 2012).

4) Applying canonical incorporation into black membranes, detergent-solubilized native phosphorylated mammalian VDAC-1 as well as recombinant channel preparations from E. coli inclusion bodies show only “open” = anion-selective = N-terminal stretch inside the barrel and “closed” = cation-selective = semi-collapsed = N-terminal stretch inside the barrel channel phenotypes (Teijido et al., 2012). “Fully closed” = collapsed = N-terminus accessible outside the barrel VDAC-1 states thus cannot be studied by this approach. The same holds true for more recent crystallization-based approaches. However, upcoming laser-based approaches may work just on native VDAC-1 in solutions; thus improvements to get detergent solubilized native VDAC preparation may pay to keep on the schedule.

--Benz R, Maier E, Thinnes FP, Götz H, Hilschmann N (1992) Studies on human porin. VII. The channel properties of the human B-lymphocyte membrane-derived “Porin 31HL” are similar to those of mitochondrial porins, Biol. Chem. Hoppe Seyler. 373: 295–303. --Thinnes FP, Burckhardt G (2012) On a fully closed state of native human type-1 VDAC enriched in Nonidet P40. Mol Genet Metab 107: 632-633. --Teijido O, Ujwal R, Hillerdal CO, Kullman L, Rostovtseva TK, Abramson J (2012) Affixing N-terminal α-helix to the wall of the voltage-dependent anion channel does not prevent its voltage gating. J Biol Chem 287: 11437-11445.