Assistant Adjunct Professor of Biochemistry, Biophysics and Structural Biology
Energy is a fundamental necessity of all living cells. Without it, cells cannot move, grow or replicate. In eukaryotic cells, energy is generated by two specialized membrane compartments (organelles), located in the cytoplasm of the cell. One is called the mitochondria, which derives cellular energy from the breakdown of food, and the other is the chloroplast, which uses the power of sunlight to generate cellular energy. Both organelles have an intricate inner membrane system which houses the proteins responsible for converting sunlight, or the energy released from the breakdown of food, into cellular energy.
The structure of the inner membrane systems is extremely important. In mitochondria, disruption of the inner membrane system is associated with many deleterious diseases in human. However, in chloroplasts and photosynthetic bacteria, alterations to the internal membrane system is an essential part of photoprotection. How these changes are achieved is currently unknown and this is exactly what the Davies’s lab is investigating. To achieve this, we use the technique of electron cryo-tomography and sub-tomogram averaging to directly determine the structure and arrangement of proteins in situ and the influence of these protein structures on membrane morphology.
Through our research, we aim to determine which proteins are responsible for inner membrane morphology; how these proteins shape the membranes; how the morphology of the inner membrane systems influence energy production, and most importantly, how the protein complexes involved in energy production interact in the membrane to generate energy efficiently. These results will uncover fundamental principles governing energy production in eurkaryotes which can then be used to develop novel approaches for curing mitochondrial diseases and designing synthetic systems for the artificial production of electricity and biomaterial.
Biogenesis of mitochondrial cristae
Mitochondria are double-membrane bound organelles located in the cytoplasm of eukaryotic cells. While the organelle’s outer membrane is smooth, the inner membrane invaginates forming multiple protrusions called cristae. The structure of the cristae varies considerably, both between species and between different tissues of the same organism. The origin of these differences and their effect on the functioning of the organelle is currently unknown. However, in previous work I have shown that the ATP synthase form rows of dimers along the highly curved edges of lamellar cristae and that these dimer rows are directly responsible for the lamellar structure (Davies et al., 2011, 2012). The Davies’s lab is now continuing this research with the aim of understanding how the ATP synthase dimers interact with the proteins involved in cristae junction formation and also how the morphology of cristae is influenced by the structure of the ATP synthase dimers and the composition of membrane lipids.
Adaptation of photosynthetic membranes to environmental changes
Cyanobacteria are the precursors to the chloroplasts of land plants and green algae. Like chloroplasts, cyanobacteria have an intricate inner membrane system which houses the proteins involved in the capture of sunlight for the generation of cellular ATP. Unlike chloroplasts and land plants, cyanobacteria can be readily modified genetically and the narrow diameter of the elongatus strains make them excellent specimens for electron cryo-tomography. Using this technique, we are investigating how changes in growth conditions influence the structure of the thylakoid membrane and the organization of proteins within them.
Assembly of bacterial microcompartments
In collaboration with Cheryl Kerfeld and Dave Savage we are using the technique of electron cryo-tomography and single particle analysis to study the assembly and heterogeneity of bacterial microcompartments. Microcompartments are proteinases icosahedral-like structures which segregate sensitive or toxic cellular reactions from the general cytoplasm of bacteria. By understanding how microcompartments assemble and function, we aim to introduce engineered microcompartments into synthetic organisms to improve the efficiency of biomass and biopolymer production.
Mühleip, A.W., Joos, J., Wigge, C., Frangakis, A.S., Kühlbrandt W., & Davies, K.M. (2016), Helical arrays of U-shaped ATP synthase dimers form tubular cristae in ciliate mitochondria, PNAS doi: 10.1073/pans.1525430113
Kukat, C., Davies, K.M., Wurm, C.A., Spahr H., Bonekamp N.A., Kühl I., Joos, F., Loguercio Polosa P., Bae Park. C., Posse, V., Falkenberg, M., Jakobs S., Kühlbrandt W., Larsson, N-G. (2015) Cross-strand binding of TFAM to a single mtDNA molecule forms the mitochondrial nucleoid PNAS, 112, 11288-93
Allegretti, M., Klusch, N., Mills, D.J., Vonck J., Kühlbrandt W.# and Davies, K.M#. (2015) Horizontal membrane-intrinsic a-helices in the stator a-subunit of an F-type ATP synthase Nature 521, 237-240, doi 10.1038/nature14185 #shared corresponding author
Davies, K.M., Anselmi, C., Wittig, I., Faraldo-Gomez, J.D., and Kuhlbrandt, W. (2012). Structure of the yeast F1Fo-ATP synthase dimer and its role in shaping the mitochondrial cristae. Proc Natl Acad Sci U S A 109, 13602-13607
Davies, K.M#., Strauss, M#., Daum, B#., Kief, J.H., Osiewacz, H.D., Rycovska, A., Zickermann, V., and Kuhlbrandt, W. (2011). Macromolecular organization of ATP synthase and complex I in whole mitochondria. Proc Natl Acad Sci U S A 108, 14121-14126. #shared first author
Photo credit: Mark Joseph Hanson of Mark Joseph Studio.
Last Updated 2016-08-21