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Science 29 August 2008:
Vol. 321. no. 5893, pp. 1206 - 1210
DOI: 10.1126/science.1161302
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Reports

Solution Structure of the Integral Human Membrane Protein VDAC-1 in Detergent Micelles

Sebastian Hiller,1 Robert G. Garces,1* Thomas J. Malia,1*{dagger} Vladislav Y. Orekhov,1,3 Marco Colombini,2 Gerhard Wagner1{ddagger}

The voltage-dependent anion channel (VDAC) mediates trafficking of small molecules and ions across the eukaryotic outer mitochondrial membrane. VDAC also interacts with antiapoptotic proteins from the Bcl-2 family, and this interaction inhibits release of apoptogenic proteins from the mitochondrion. We present the nuclear magnetic resonance (NMR) solution structure of recombinant human VDAC-1 reconstituted in detergent micelles. It forms a 19-stranded β barrel with the first and last strand parallel. The hydrophobic outside perimeter of the barrel is covered by detergent molecules in a beltlike fashion. In the presence of cholesterol, recombinant VDAC-1 can form voltage-gated channels in phospholipid bilayers similar to those of the native protein. NMR measurements revealed the binding sites of VDAC-1 for the Bcl-2 protein Bcl-xL, for reduced β–nicotinamide adenine dinucleotide, and for cholesterol. Bcl-xL interacts with the VDAC barrel laterally at strands 17 and 18.

1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Biology, University of Maryland, College Park, MD 20742, USA.
3 Swedish NMR Centre, University of Gothenburg, Box 465, 40530 Gothenburg, Sweden.

* These authors contributed equally to this work.

{dagger} Present address: Centocor, Incorporated, Radnor, PA 19087, USA.

{ddagger} To whom correspondence should be addressed. E-mail: gerhard_wagner{at}hms.harvard.edu

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