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

TLDR

VDAC mediates trafficking of small molecules and ions across the eukaryotic outer mitochondrial membrane and interacts with anti‑apoptotic Bcl‑2 family proteins to inhibit release of apoptogenic proteins. The authors determined the NMR solution structure of recombinant human VDAC‑1 reconstituted in detergent micelles. The structure reveals a 19‑stranded β‑barrel with parallel terminal strands, a detergent belt covering the hydrophobic exterior, and, in the presence of cholesterol, the protein forms voltage‑gated channels in phospholipid bilayers; NMR identified binding sites for Bcl‑xL, NADH, and cholesterol, with Bcl‑xL binding laterally at strands 17 and 18.

Abstract

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-x L , for reduced β–nicotinamide adenine dinucleotide, and for cholesterol. Bcl-x L interacts with the VDAC barrel laterally at strands 17 and 18.