title: Functional model of metabolite gating by human voltage-dependent anion channel 2.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, Department of Biological Sciences, New York, New York 10027, United States.
authors.forename: Andras J
authors.initials: AJ
authors.lastname: Bauer
authors.forename: Simone
authors.initials: S
authors.lastname: Gieschler
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Lemberg
authors.forename: Ann E
authors.initials: AE
authors.lastname: McDermott
authors.forename: Brent R
authors.initials: BR
authors.lastname: Stockwell
mesh_terms: D006801:Humans; D015640:Ion Channel Gating; D008081:Liposomes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009243:NAD / Q000737:chemistry; D010539:Permeability; D010713:Phosphatidylcholines / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry; D050996:Voltage-Dependent Anion Channel 2 / Q000737:chemistry*
chemical_list: D008081:Liposomes; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D010879:Piperazines; D011994:Recombinant Proteins; C494765:VDAC2 protein, human; D050996:Voltage-Dependent Anion Channel 2; C477224:erastin; D009243:NAD