Sergey M. Bezrukov, Ph.D.
Section on Molecular Transport
Building 9, Room 1N124
9 Memorial Drive
Bethesda, MD 20892
We study mechanisms of transporter-facilitated metabolite exchange across cell and organelle membranes by combining physical theory and experiments on reconstitution of the corresponding “large” ion channels into planar lipid membranes. It is well-recognized that disturbances in metabolite transport result in a wide variety of pathologies in development and in different organ systems, including, among others, cancer, cystic fibrosis, seizure disorders, muscular dystrophies, and cardiomyopathies. Understanding of the physical mechanisms that govern metabolite transport is essential for creating new approaches to treatment of these pathologies.
To investigate channels under precisely controlled conditions, we first isolate the channel-forming proteins from their host organisms, then purify and reconstitute them into planar lipid membranes. Our main goal is to elucidate the physical principles and molecular mechanisms responsible for metabolite flux regulation under normal and pathological conditions. The channel-forming proteins of interest include the voltage-dependent anion channel from the outer membrane of mitochondria (VDAC), B-components of Clostridium botulinum C2 and Clostridium perfringens iota toxins, Bacillus anthracis protective antigen, Clostridium perfringens epsilon toxin, Escherichia coli general porin OmpF and sugar-specific LamB, Staphylococcus aureus alpha-hemolysin, Pseudomonas aeruginosa OprF, Trichoderma viride alamethicin, and Pseudomonas syringae lipopeptide toxin syringomycin E. We also use Bacillus brevis gramicidin A as a tool to study mechanical properties of lipid membranes.
Rostovtseva TK, Gurnev PA, Protchenko O, Hoogerheide DP, Yap TL, Philpott CC, Lee JC, Bezrukov SM. α-Synuclein Shows High Affinity Interaction with Voltage-dependent Anion Channel, Suggesting Mechanisms of Mitochondrial Regulation and Toxicity in Parkinson Disease. J Biol Chem. 2015;290(30):18467-77.
Berezhkovskii AM, Dagdug L, Bezrukov SM. Discriminating between anomalous diffusion and transient behavior in microheterogeneous environments. Biophys J. 2014;106(2):L09-11.
Nestorovich EM, Karginov VA, Popoff MR, Bezrukov SM, Barth H. Tailored ß-cyclodextrin blocks the translocation pores of binary exotoxins from C. botulinum and C. perfringens and protects cells from intoxication. PLoS One. 2011;6(8):e23927.
Gurnev PA, Rostovtseva TK, Bezrukov SM. Tubulin-blocked state of VDAC studied by polymer and ATP partitioning. FEBS Lett. 2011;585(14):2363-6.
Sheldon KL, Maldonado EN, Lemasters JJ, Rostovtseva TK, Bezrukov SM. Phosphorylation of voltage-dependent anion channel by serine/threonine kinases governs its interaction with tubulin. PLoS One. 2011;6(10):e25539.