Dr. William Dowhan, Professor
and Holder of the John S. Dunn, Sr. Chair

Structure, Function and Assembly of Cell Membranes

A combined molecular genetic and biochemical approach is being used to study the structure, function, and biogenesis of biological membranes in prokaryotic (E. coli) and eukaryotic (yeast) microorganisms. Studies utilizing E. coli focus on understanding biological processes that are similar in both simple and complex organisms. A major goal is to understand the role individual phospholipid species and general membrane phospholipid composition play in cell function. Specific roles for phospholipids at the molecular level have been defined for translocation of proteins across membranes, energy transduction processes, signal transduction, cell division, and the assembly and function of integral membrane proteins. A major emphasis is to understand how membrane proteins interact with their lipid environment to attain final topological organization.

Studies using yeast focus on problems that are unique to eukaryotic systems. Mutants in phospholipid metabolism are being used to study the roles of mitochondrial-specific anionic phospholipids cardiolipin and phosphatidylglycerol in the synthesis, assembly, and function of mitochondrial membrane proteins. A primary role of cardiolipin is to organize components of the electron transport system into supermolecular complexes while both anionic phospholipids are required for the translation of nuclear- and mitochondrial-encoded components of the electron transport chain. View Extended Description of Research Objectives

Simoni, R. and Mukhopadhyay, R. Exploring the world of phospholipids and their interactions with proteins: The work of William Dowhan.J. Biol. Chem. 287(12): 9509., 2012.

Zhang, J., Guan, Z., Murphy, A. N., Wiley, S. E., Perkins, G. A., Worby, C .A., Engel, J. L., Heacock, P., Nguyen, O. K., Wang, J. H., Raetz, C. R. H., Dowhan, W., Dixon, J. E. Mitochondrial Phosphatase PTPMT1 Is Essential for Cardiolipin Biosynthesis. Cell Metabolism 13: 690-700, 2011.

Vitrac, H., Bogdanov, M., Heacock, P. and Dowhan, W. Lipids and topological rules of membrane protein assembly: balance between long- and short-range lipid-protein interactions. J. Biol. Chem. 286: 15182-15194, 2011.

Bogdanov M, Heacock P, Guan Z, Dowhan W. Plasticity of lipid-protein interactions in the function and topogenesis of the membrane protein lactose permease from Escherichia coli. Proc Natl Acad Sci U S A. 107:15057-62, 2010.

Bogdanov, M., Heacock, P. and Dowhan, W.: Study of polytopic membrane protein topological organization as a function of membrane lipid composition. Protein Secretion, Methods in Molecular Biology, ed. Economou, A. (Springer, New York), Vol 619, pp 79-101, 2010.

Dowhan W, Bogdanov M. Lipid-dependent membrane protein topogenesis. Annu Rev Biochem. 78:515-40, 2009.

Mileykovskaya, E., Ryan, A. C., Mo, X., Lin, C.-C., Khalaf, K. I., Dowhan W., and Garrett, T. A.: Phosphatidic acid and N-acyl phosphatidylethanolamine form membrane domains in Escherichia coli. J. Biol. Chem. 284: 2990-3000, 2009.

Kutik, S., Rissler, M., Xue Li Guan, X.-L., Guiard, B., Shui, G., Gebert,N., Heacock, P. N., Rehling, P., Dowhan, W., Wenk, M. R., Pfanner, N., and Wiedemann, N.: The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis. J. Cell Biol. 183:1213-21, 2009.

Dowhan, W.: Molecular Genetic Approaches to Defining Lipid Function. J. Lipid Res. 50: S305–S310. 2009.

Bogdanov, M., Jun, X. and Dowhan, W.: Lipid-protein interactions drive membrane protein topogenesis in accordance with the positive-inside rule. (Mini Review) J. Biol. Chem. 284: 9637-9641,2009.

Mileykovskaya, E. and Dowhan, W.: Cardiolipin domains in prokaryotes and eukaryotes. Biochim. Biophys. Acta-Biomembranes 1778:2084-91, 2009.

Wikström, M., Kelly, A. A., Georgiev, A., Eriksson, H. M., Klement, M. R., Bogdanov, M., Dowhan, W., and Wieslander, Å.:Lipid-engineered Escherichia coli membranes reveal critical headgroup size for protein function. J. Biol. Chem. 284: 954-965, 2009.

Bogdanov, M., Xie, J., Heacock, P. and Dowhan, W.: To flip or not to flip: lipid-protein charge interactions are a determinant of final membrane protein topology. J. Cell Biol. 182: 925-935, 2008.

Xie, J., Bogdanov, M., Heacock, P. and Dowhan, W.: Phosphatidylethanolamine and monoglucosyldiacylglycerol are interchangeable in supporting topogenesis and function of the polytopic membrane protein lactose permease. J. Biol. Chem. 281: 19172-19178, 2006.

Su, X. and Dowhan, W.: Translational Regulation of Nuclear Gene COX4 Expression by Mitochondrial Content of Phosphatidylglycerol and Cardiolipin in Saccharomyces cerevisiae. Mol. Cell. Biol. 26: 743-753, 2006.

Zhang, M, Mileykovskaya, E. and Dowhan, W.: Cardiolipin is essential for organization of complexes III and IV into a supercomplex in intact yeast mitochondria. J. Biol. Chem. 280: 29403-29408, 2005.

Bogdanov, M., Zhang, W., Xie, J., and Dowhan, W.: “Transmembrane protein topology mapping by the substituted cysteine accessibility method (SCAMTM): Application to lipid-specific membrane protein topogenesis.” Methods 36: 148-171, 2005.

Mileykovskaya, E., Fishov, I., Fu, X., Corbin, B. D., Margolin, W., and Dowhan, W.: Effects of phospholipid composition on MinD-membrane interactions in vitro and in vivo. J. Biol. Chem. 278:22193-22198, 2003.

Zhang, M., Mileykovskaya, E., and Dowhan, W.: Gluing the Respiratory Chain Together: Cardiolipin Is Required for Supercomplex Formation in the Inner Mitochondrial Membrane. J. Biol. Chem. 277, 43553-43556, 2002.

Search PubMed for a complete list of Dr. Dowhan's publications.