Magic angle spinning nuclear magnetic resonance characterization of voltage-dependent anion channel gating in two-dimensional lipid crystalline bilayers

Biochemistry. 2015 Feb 3;54(4):994-1005. doi: 10.1021/bi501260r. Epub 2015 Jan 16.

Abstract

The N-terminus of the voltage-dependent anion channel (VDAC) has been proposed to contain the mechanistically important gating helices that modulate channel opening and closing. In this study, we utilize magic angle spinning nuclear magnetic resonance (MAS NMR) to determine the location and structure of the N-terminus for functional channels in lipid bilayers by measuring long-range (13)C-(13)C distances between residues in the N-terminus and other domains of VDAC reconstituted into DMPC lipid bilayers. Our structural studies show that the distance between A14 Cβ in the N-terminal helix and S193 Cβ is ∼4-6 Å. Furthermore, VDAC phosphorylation by a mitochondrial kinase at residue S193 has been claimed to delay mitochondrial cell death by causing a conformational change that closes the channel, and a VDAC-Ser193Glu mutant has been reported to show properties very similar to those of phosphorylated VDAC in a cellular context. We expressed VDAC-S193E and reconstituted it into DMPC lipid bilayers. Two-dimensional (13)C-(13)C correlation experiments showed chemical shift perturbations for residues located in the N-terminus, indicating possible structural perturbations to that region. However, electrophysiological data recorded on VDAC-S193E showed that channel characteristics were identical to those of wild type samples, indicating that phosphorylation of S193 does not directly affect channel gating. The combination of NMR and electrophysiological results allows us to discuss the validity of proposed gating models.

Publication types

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

MeSH terms

  • Crystallization
  • Humans
  • Ion Channel Gating / physiology
  • Lipid Bilayers / chemistry*
  • Lipid Bilayers / metabolism*
  • Magnetic Resonance Spectroscopy / methods*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Voltage-Dependent Anion Channel 1 / chemistry*
  • Voltage-Dependent Anion Channel 1 / metabolism*

Substances

  • Lipid Bilayers
  • VDAC1 protein, human
  • Voltage-Dependent Anion Channel 1