Oded Lewinson, PhD
Assistant Professor of Microbiology
PhD, 2005 - Weizmann Institute, Israel
Structure and function of membrane embedded transport proteins
The selectivity barrier created by biological membranes is essential to all life forms as it defines the interface between ‘self’ and the environment. All organisms control the distribution of metabolites and toxic materials across their cellular membranes. The active generation of chemical and electrical concentration gradients is achieved through the action of membrane embedded enzymes called transporters. In my lab, we study the structure-function relations of these elaborate molecular machines, focusing on transporters that use ATP as their energy source. One such group of special interest and importance is transporters of transition metals. Transition metals are essential cofactors for about a third of all enzymes and accordingly, are crucial micronutrients for all organisms. On the other hand, their intracellular overload is highly toxic and therefore homeostasis of transition metals is a delicate balance between acquiring the essential quota and avoiding undesired toxic effects. To combat infections, mammalian hosts use both transition metal sequestering and bombardment strategies. It is thus not surprising that bacterial pathogens have developed an intricate and diverse array of metal efflux and influx pumps to maintain and control their quota of transition metals (Figure 1). These transporters are pivotal virulence determinants of important human pathogens such as Mycobacterium tuberculosis, Staphylococcus aureus, Streptococcus pneumonia, Bacillus anthracis, and Salmonella typhi. We study the mechanism of action of these transporters and try to understand their role in bacterial virulence.
Vigonsky E, Fish I, Livnat-Levanon N, Ovcharenko E, Ben-Tal N, and Lewinson O. 2015. Metal binding spectrum and model structure of the Bacillus anthracis virulence determinant MntA. Metallomics [Epub ahead of print].
Lee JY, Yang JG, Zhitnitsky D, Lewinson O, and Rees DC. 2014. Structural basis for heavy metal detoxification by an Atm1-Type ABC exporter. Science 343, 1133-6.
Tal N, Ovcharenko E, and Lewinson O. 2013. A single intact ATPase site of the ABC transporter BtuCD drives 5% transport activity yet supports full in-vivo vitamin B12 utilization. Proc. Natl. Acad. Sci. USA 110, 5434-5439.
Vigonsky E, Ovcharenko E, and Lewinson O. 2013. Two molybdate/tungstate ABC transporters that interact very differently with their substrate binding proteins. Proc. Natl. Acad. Sci. USA 110, 5440-5445
Klein JS and Lewinson O. 2011. Bacterial ATP-driven transporters of transition metals: physiological roles, mechanisms of action, and roles in bacterial virulence. Metallomics 3, 1098-108.
Schematic illustration of the different transporter types participating in transition metal translocation in gram-negative bacteria.
Arrows indicate the directionality of proton and transition metal transport. From left to right: RND transporters have a trimeric organization and traverse both the inner and outer membranes. They utilize the energetically downhill movement of protons across the inner membrane to drive metal efflux from the cytosol and the periplasm to the cell exterior. ABC transporters have a dimeric organization and are embedded in the inner membrane. They use the energy of ATP hydrolysis and require a cognate substrate binding protein for their function. ABC transporters partner with the energy-transducing ExbB/ExbD/TonB and high affinity outer membrane transporters to deliver essential trace elements from the environment to the cytosol. P-type ATPases are monomers, and like ABC transporters, are powered by ATP to catalyze metal efflux from the cytosol, across the inner membrane, to the periplasm. A similar task is performed by the dimeric CDF transporters that utilize the energy of ΔμH+ to drive metal efflux across the inner membrane.