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

Autor: Rosencrans WM; Section on Molecular Transport, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA., Aguilella VM; Laboratory of Molecular Biophysics, Department of Physics, Universitat Jaume I, Av. Vicent Sos Baynat s/n 12071, Castellón, Spain., Rostovtseva TK; Section on Molecular Transport, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA. Electronic address: rostovtt@mail.nih.gov., Bezrukov SM; Section on Molecular Transport, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
Jazyk: angličtina
Zdroj: Cell calcium [Cell Calcium] 2021 May; Vol. 95, pp. 102355. Date of Electronic Publication: 2021 Feb 02.
DOI: 10.1016/j.ceca.2021.102355
Abstrakt: Voltage-dependent anion channel (VDAC) is the most ubiquitous channel at the mitochondrial outer membrane, and is believed to be the pathway for calcium entering or leaving the mitochondria. Therefore, understanding the molecular mechanisms of how VDAC regulates calcium influx and efflux from the mitochondria is of particular interest for mitochondrial physiology. When the Parkinson's disease (PD) related neuronal protein, alpha-synuclein (αSyn), is added to the reconstituted VDAC, it reversibly and partially blocks VDAC conductance by its acidic C-terminal tail. Using single-molecule VDAC electrophysiology of reconstituted VDAC we now demonstrate that, at CaCl 2 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. -Our findings with higher calcium concentrations also demonstrate that the phenomenon of "charge inversion" is taking place at the level of a single polypeptide chain. Measurements of ion selectivity of three VDAC isoforms in CaCl 2 gradient show that VDAC3 exhibits the highest calcium permeability among them, followed by VDAC2 and VDAC1, thus pointing to isoform-dependent physiological function. Mutation of the E73 residue - VDAC1 purported calcium binding site - shows that there is no measurable effect of the mutation in either open or αSyn-blocked VDAC1 states. Our results confirm VDACs involvement in calcium signaling and reveal a new regulatory role of αSyn, with clear implications for both normal calcium signaling and PD-associated mitochondrial dysfunction.
(Published by Elsevier Ltd.)
Databáze: MEDLINE
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