Crystal packing analysis of murine VDAC1 crystals in a lipidic environment reveals novel insights on oligomerization and orientation

Channels (Austin). 2009 May-Jun;3(3):167-70. doi: 10.4161/chan.3.3.9196. Epub 2009 May 15.

Abstract

All eukaryotic cells require efficient trafficking of metabolites between the mitochondria and the rest of the cell. This exchange is carried out by the dominant protein in the outer mitochondrial membrane (OMM), the Voltage Dependent Anion Channel (VDAC), which serves as the primary pathway for the exchange of ions and metabolites between the cytoplasm and the intermembrane space of the mitochondria. Additionally, VDAC provides a scaffold for the binding of modulator proteins to the mitochondria and has been implicated in mitochondria-dependent cell death. We recently determined the structure of the murine VDAC1 (mVDAC1) at 2.3 A resolution crystallized in a native-like bilayer environment. The high-resolution structure provided concise structural details about the voltage-sensing N-terminal domain and catalyzed new hypotheses regarding the gating mechanisms for metabolites and ions that transit the OMM. In this study, the crystal packing of mVDAC1 is analyzed revealing a strong antiparallel dimer that further assemble as hexamers mimicking the native oligomeric packing observed in EM and AFM images of the OMM. Oligomerization has been shown to be important for VDAC regulation and function, and mVDAC1 crystal packing in a lipidic medium reveals insights on how oligomerization is accomplished using protein-protein and protein-lipid interactions. Furthermore, orientation of VDAC in the OMM remains uncertain due to inconsistencies in antibody labeling studies. The physiological implications of a novel antiparallel arrangement are addressed that may clarify these conflicting biochemical data.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Membrane Lipids / chemistry*
  • Membrane Lipids / metabolism
  • Mice
  • Protein Multimerization / physiology*
  • Protein Structure, Quaternary / physiology
  • Protein Structure, Tertiary / physiology
  • Structure-Activity Relationship
  • Voltage-Dependent Anion Channel 1 / chemistry*
  • Voltage-Dependent Anion Channel 1 / metabolism

Substances

  • Membrane Lipids
  • Vdac1 protein, mouse
  • Voltage-Dependent Anion Channel 1