Functional Model of Metabolite Gating by Human Voltage-Dependent Anion Channel 2

Voltage-dependent anion channels (VDACs) are critical regulators of outer mitochondrial membrane permeability in eukaryotic cells. VDACs have also been postulated to regulate cell death mechanisms. Erastin, a small molecule quinazolinone that is selectively lethal to tumor cells expressing mutant RA...

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Bibliographic Details
Published in:Biochemistry (Easton) 2011-05, Vol.50 (17), p.3408-3410
Main Authors: Bauer, Andras J, Gieschler, Simone, Lemberg, Kathryn M, McDermott, Ann E, Stockwell, Brent R
Format: Article
Language:English
Subjects:
Humans
Ion Channel Gating
Liposomes - chemistry
Magnetic Resonance Spectroscopy
Models, Molecular
NAD - chemistry
Permeability
Phosphatidylcholines - chemistry
Phosphatidylserines - chemistry
Piperazines - chemistry
Protein Folding
Protein Structure, Secondary
Rapid Report
Recombinant Proteins - chemistry
Voltage-Dependent Anion Channel 2 - chemistry
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Summary:Voltage-dependent anion channels (VDACs) are critical regulators of outer mitochondrial membrane permeability in eukaryotic cells. VDACs have also been postulated to regulate cell death mechanisms. Erastin, a small molecule quinazolinone that is selectively lethal to tumor cells expressing mutant RAS, has previously been reported as a ligand for hVDAC2. While significant efforts have been made to elucidate the structure and function of hVDAC1, structural and functional characterization of hVDAC2 remains lacking. Here, we present an in vitro system that provides a platform for both functional and structural investigation of hVDAC2 and its small molecule modulator, erastin. Using this system, we found that erastin increases permeability of VDAC2 liposomes to NADH in a manner that requires the amino-terminal region of VDAC2. Furthermore, we confirmed that this VDAC2-lipsome sample is folded using solid-state NMR.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi2003247