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Solution structure of the integral human membrane protein VDAC-1 in detergent micelles

Sebastian Hiller1, Robert G Garces, Thomas J Malia

  • 1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Science (New York, N.Y.)
|August 30, 2008
PubMed

Insights

The voltage-dependent anion channel (VDAC) structure was determined using NMR. This reveals how VDAC interacts with cholesterol and Bcl-x(L) to regulate mitochondrial function and apoptosis.

Area of Science:

  • Biophysics
  • Structural Biology
  • Molecular Biology

Background:

  • The voltage-dependent anion channel (VDAC) is crucial for mitochondrial membrane transport.
  • VDAC interacts with Bcl-2 proteins, inhibiting apoptosis.
  • Understanding VDAC structure is key to its function in cell death regulation.

Purpose of the Study:

  • To determine the solution structure of human VDAC-1.
  • To investigate VDAC-1 interactions with cholesterol and Bcl-x(L).
  • To elucidate the structural basis for VDAC's role in apoptosis.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy was used to determine the solution structure.
  • Recombinant human VDAC-1 was reconstituted in detergent micelles.
  • Binding sites for ligands were identified using NMR.

Main Results:

  • The structure of human VDAC-1 is a 19-stranded beta barrel.
  • VDAC-1 forms voltage-gated channels in phospholipid bilayers with cholesterol.
  • NMR identified binding sites for Bcl-x(L), NADH, and cholesterol.
  • Bcl-x(L) binds laterally to VDAC strands 17 and 18.

Conclusions:

  • The NMR structure provides insights into VDAC-1's function.
  • Cholesterol is essential for VDAC-1 channel activity.
  • VDAC-1's interaction with Bcl-x(L) is structurally defined, impacting apoptosis.

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