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α-Synuclein emerges as a potent regulator of VDAC-facilitated calcium transport

William M. Rosencrans, Vicente M. Aguilella, Tatiana K. Rostovtseva, Sergey M. Bezrukov
doi: https://doi.org/10.1101/2020.11.15.383729
William M. Rosencrans
1Section on Molecular Transport, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
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Vicente M. Aguilella
2Laboratory of Molecular Biophysics, Department of Physics, Universitat Jaume I, Av. Vicent Sos Baynat s/n 12071, Castellón, Spain
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Tatiana K. Rostovtseva
1Section on Molecular Transport, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
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  • For correspondence: rostovtt@mail.nih.gov
Sergey M. Bezrukov
1Section on Molecular Transport, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
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Abstract

When the Parkinson’s disease (PD) related neuronal protein, alpha-synuclein (αSyn), is added to the reconstituted mitochondrial voltage-dependent anion channel (VDAC), it reversibly and partially blocks VDAC conductance by its acidic C-terminal tail. Using single-molecule electrophysiology of reconstituted VDAC we now demonstrate that, at CaCl2 concentrations below 150 mM, αSyn reverses the channel’s selectivity from anionic to cationic. Importantly, we find that the decrease in channel conductance upon its blockage by αSyn is hugely overcompensated by a favorable change in the electrostatic environment for calcium, making the blocked state orders-of-magnitude more selective for calcium and thus increasing its net flux. These findings reveal a new regulatory role of αSyn, with clear implications for both normal calcium signaling and PD-associated mitochondrial dysfunction.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted November 16, 2020.
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α-Synuclein emerges as a potent regulator of VDAC-facilitated calcium transport
William M. Rosencrans, Vicente M. Aguilella, Tatiana K. Rostovtseva, Sergey M. Bezrukov
bioRxiv 2020.11.15.383729; doi: https://doi.org/10.1101/2020.11.15.383729
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α-Synuclein emerges as a potent regulator of VDAC-facilitated calcium transport
William M. Rosencrans, Vicente M. Aguilella, Tatiana K. Rostovtseva, Sergey M. Bezrukov
bioRxiv 2020.11.15.383729; doi: https://doi.org/10.1101/2020.11.15.383729

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