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Published on: June 1, 2022
Modulation of the mitochondrial voltage dependent anion channel (VDAC) by curcumin
Debanjan Tewari1, Tofayel Ahmed1, Venkat R Chirasani1
1Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences Building, Indian Institute of Technology Madras, Chennai 600036, India.
Abstract:
Voltage dependent anion channel (VDAC) of mitochondria plays a crucial role in apoptosis. Human VDAC-1, reconstituted in planar lipid bilayer showed reduced conductance when treated with curcumin. Curcumin interacts with residues in the α helical N-terminus of VDAC and in the channel wall, as revealed by molecular docking, followed by mutational analysis. N-terminus mimicking peptide showed conformational changes in circular dichroism, upon curcumin treatment. We propose that the interaction of curcumin with amino acids in N-terminus and in channel wall fixes the α helix in closed conformation. This restricts its movement which is required for the opening of the channel.
Insights
Curcumin reduces mitochondrial VDAC-1 channel conductance by binding to its N-terminus and channel wall. This interaction stabilizes the channel in a closed conformation, inhibiting its function in apoptosis.
Area of Science:
- Mitochondrial biology
- Biophysics
- Molecular pharmacology
Background:
- Voltage-dependent anion channel (VDAC) is critical for mitochondrial function and apoptosis.
- Curcumin, a natural compound, has shown potential in modulating cellular processes.
Purpose of the Study:
- To investigate the effect of curcumin on human VDAC-1 channel activity.
- To elucidate the molecular mechanism of curcumin interaction with VDAC-1.
Main Methods:
- Reconstitution of human VDAC-1 in planar lipid bilayers.
- Electrophysiological measurements of channel conductance.
- Molecular docking simulations.
- Site-directed mutagenesis.
- Circular dichroism spectroscopy of VDAC-1 N-terminus peptide.
Main Results:
- Curcumin treatment significantly reduced the conductance of VDAC-1 reconstituted in lipid bilayers.
- Molecular docking and mutational analysis identified curcumin binding sites in the VDAC-1 N-terminus and channel wall.
- Circular dichroism revealed conformational changes in the VDAC-1 N-terminus peptide upon curcumin exposure.
- These findings suggest curcumin stabilizes VDAC-1 in a closed conformation.
Conclusions:
- Curcumin directly interacts with human VDAC-1, inhibiting its channel activity.
- The interaction involves the N-terminus and channel wall, leading to a closed channel conformation.
- This mechanism provides insight into curcumin's role in regulating mitochondrial function and apoptosis.
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