Functional investigations of the human voltage-dependent anion channel 1 by solid-state NMR spectroscopy

• Applicant: Dr. Robert Silvers
• Subject Area: Structural Biology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280480342

Membrane proteins can provide pathways through a bilayer leaflet for a variety of ligands and often do so in a switchable fashion. Metabolite transport across the mitochondrial outer membrane (MOM) is essential for fulfilling the energy requirements of living cells. The voltage-dependent anion channel (VDAC) is the most abundant protein of the MOM and is known to be the primary avenue for metabolite traffic between the mitochondrion and cytoplasm. The 283-residue hVDAC1 has emerged as a potential switch determining the onset of mitochondria-relayed apoptosis. Thus, knowledge of the gating mechanism should provide a target for development of small molecules that have pro-apoptotic activity and potential as antitumor agents.The main research objective of this project is the structural and functional study of hVDAC1 in its natural environment, i.e. lipid bilayers, where it is folded, stable over wide pH range, and is known to exhibit channel activity. In order to achieve these goals, a plethora of solid-state NMR spectroscopic experiments is planned, including 2D homo- and heteronuclear correlation spectra as well as 3D assignment experiments. State-of-the-art proton detection will be used to further improve structural and functional information. Besides the structures of VDAC in its open and closed conformation, the interaction of VDAC with small ligands (ATP/NADH) as well as biomacromolecules, such as hexokinase, is planned.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Robert G. Griffin