So similar, yet so different: α-synuclein recognition of the isoform-specific VDAC protein-lipid interface
- 1NICHD, NIH
Abstract
In mammals, VDAC exists as three isoforms--VDAC1, VDAC2, and VDAC3--each characterized by a distinct tissue-dependent distribution and physiologic role. Isoform-specific knockout studies in cells and mice demonstrate distinct physiological roles for each VDAC isoform. The isoforms share about 70% sequence homology and a conserved {beta}-barrel structure and, when reconstituted into planar lipid membranes, form similar highly conductive, anion-selective, voltage-gated channels. A natural question, then, is how relatively minor differences in isoform sequences lead to striking differences in their interactions with protein partners and, consequently, in their physiological functions. To address this question, we used a small, intrinsically disordered cytosolic protein -synuclein (Syn) as a sensitive molecular probe. A comparative study with recombinant VDACs reconstituted into planar lipid membranes shows that, depending on the isoform, the Syn-induced blockage exhibits up to 100-fold differences in on-rates and equilibrium constants. The isoforms also display distinct translocation regimes for Syn, as evidenced by altered dependences of the off-rates on the applied voltage. Deletion of cysteine residues has a significant effect on Syn binding. Combined with corresponding data obtained for VDAC2 substates--which show an order of magnitude variation in on-rates while maintaining the conserved equilibrium constants--and the results of molecular dynamics simulations, these findings point to a previously unrecognized step in VDAC inhibition by Syn: an isoform-specific Syn interaction with the VDAC protein-lipid interface. This finding opens a new paradigm for understanding VDAC isoform functions and developing isoform-specific therapeutics.
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BibTeX
@misc{rostovtseva2026similar,
title = {{So similar, yet so different: α-synuclein recognition of the isoform-specific VDAC protein-lipid interface}},
author = {T. K. Rostovtseva and M. Rajendran and W. M. Rosencrans and M. Queralt-Martin and M. S. Wolfe and N. A. Bautista and B. G. Beyene and M. G. Larimi and A. J. Sodt and S. M. Bezrukov},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.758914},
url = {https://www.biorxiv.org/content/10.64898/2026.10.13.758914v1},
note = {CC0},
}
RIS
TY - UNPB
TI - So similar, yet so different: α-synuclein recognition of the isoform-specific VDAC protein-lipid interface
AU - T. K. Rostovtseva
AU - M. Rajendran
AU - W. M. Rosencrans
AU - M. Queralt-Martin
AU - M. S. Wolfe
AU - N. A. Bautista
AU - B. G. Beyene
AU - M. G. Larimi
AU - A. J. Sodt
AU - S. M. Bezrukov
PY - 2026
DA - 2026/10/13
PB - bioRxiv
DO - 10.64898/2026.10.13.758914
UR - https://www.biorxiv.org/content/10.64898/2026.10.13.758914v1
AB - In mammals, VDAC exists as three isoforms--VDAC1, VDAC2, and VDAC3--each characterized by a distinct tissue-dependent distribution and physiologic role. Isoform-specific knockout studies in cells and mice demonstrate distinct physiological roles for each VDAC isoform. The isoforms share about 70% sequence homology and a conserved {beta}-barrel structure and, when reconstituted into planar lipid membranes, form similar highly conductive, anion-selective, voltage-gated channels. A natural question, then, is how relatively minor differences in isoform sequences lead to striking differences in their interactions with protein partners and, consequently, in their physiological functions. To address this question, we used a small, intrinsically disordered cytosolic protein -synuclein (Syn) as a sensitive molecular probe. A comparative study with recombinant VDACs reconstituted into planar lipid membranes shows that, depending on the isoform, the Syn-induced blockage exhibits up to 100-fold differences in on-rates and equilibrium constants. The isoforms also display distinct translocation regimes for Syn, as evidenced by altered dependences of the off-rates on the applied voltage. Deletion of cysteine residues has a significant effect on Syn binding. Combined with corresponding data obtained for VDAC2 substates--which show an order of magnitude variation in on-rates while maintaining the conserved equilibrium constants--and the results of molecular dynamics simulations, these findings point to a previously unrecognized step in VDAC inhibition by Syn: an isoform-specific Syn interaction with the VDAC protein-lipid interface. This finding opens a new paradigm for understanding VDAC isoform functions and developing isoform-specific therapeutics.
ER -