New findings concerning vertebrate porin II ¡ª On the relevance of glycine motifs of type-1 VDAC

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• 作者：Friedrich P. Thinnes ^{futhin@t-online.de}
• 关键词：Eryptosis ; Down Syndrome ; Parkinson's disease ; Amyotrophic Lateral Sclerosis ; Cystic fibrosis ; Malaria
• 刊名：Molecular Genetics and Metabolism
• 出版年：2013
• 出版时间：April, 2013
• 年：2013
• 卷：108
• 期：4
• 页码：212-224
• 全文大小：2006 K

文摘

New findings concerning vertebrate porin part I was published in 1997, then summarizing early data and reflections regarding the molecular structure of vertebrate voltage-dependent anion-selective channels, VDAC/eukaryotic porin, and the extra-mitochondrial expression pattern of human type-1 VDAC. Meanwhile, endeavors of different laboratories confirmed and widened this beginning by encircling the function of the channels. Regarding the function of mitochondrial outer membrane-standing VDACs the channels are established parts of the intrinsic apoptotic pathway and thus therapeutic targets in studies on several diseases: cancer, Alzheimer's disease, Down Syndrome, Parkinson's disease, Amyotrophic Lateral Sclerosis, cystic fibrosis and malaria. Regarding cell membrane-integrated type-1 VDAC it has been documented by different approaches that this porin channel is engaged in cell volume regulation, trans-membrane electron transport and apoptosis. Furthermore, new data insinuate a bridging of extrinsic and intrinsic apoptotic pathways, putatively gaining relevance in Alzheimer research. Mammalian type-1 VDAC, a ¦Â-barrel, is basically built up by nineteen ¦Â-sheets connected by peptide stretches of varying lengths. The molecule also comprises an N-terminal stretch of some twenty amino acids which, according to biochemical data, traverses the channel lumen towards the cytosolic surface of outer mitochondrial membranes or the plasma lemma, respectively and works as voltage sensor in channel gating. In artificial lipid bilayers VDACs figure as anion or cation-channels, as VDACs are permeable to both cations and anions, with voltage shifts changing the relative permeability. Type-1 VDAC carries several motifs where glycine residues are in critical positions. Motifs of this type, on the on hand, are established nucleotide binding sites. On the other hand, the GxxxG motifs are also discussed as relevant peptide dimerization/aggregation/membrane perturbation motifs. Finally, GxxxG motifs bind cholesterol. Type-1 VDAC shows one such GxxxG motif at the proximal end of its N-terminal voltage sensor while amyloid A¦Â peptides include three of them in series. Noteworthy, two additional may be modified versions, GxxxGxG and GxxGxxxG, are found on ¦Â-sheet 19 or 9, respectively. Recent data have allowed speculating that amyloid A¦Â induces apoptosis via opening type-1 VDAC in cell membranes of hypo-metabolic neurons, a process most likely running over life time - as leaves fall from trees in the tropics - and ending in Alzheimer's disease whenever critical brain regions are affected. The expression of GxxxG motifs on either reactant under consideration is in line with this model of Alzheimer's disease pathogenesis, which clearly differs from the amyloid A¦Â cascade theory, and which can, furthermore, be understood as a basic model for apoptosis induction. However, to assume randomly distributed interactions of body wide found amyloid A¦Â peptides with the N-terminal voltage sensors of ubiquitously expressed cell membrane-standing human type-1 VDAC opens up a new view on Alzheimer's disease, which might even include a clue on systemic aspects of the disease. While elaborating this concept, my focus was at first only on the GxxxG motif at the proximal end of the N-terminal voltage sensor of type-1 VDAC. Here, I include a corresponding sequence stretch on the channel's ¦Â-sheet 19, too.