Structure determination and functional studies of macromolecular assemblies using 3DEM
Dr. Radermacher received in Ph.D. in Physics at the Max-Planck-Institute for Biochemistry and the Technical University Munich (GER).
He joined the UVM faculty in 2002.
Our laboratory studies the structure and function of enzyme complexes in the mitochondrial respiratory chain by 3D electron microscopy. Our main emphasis is on the structure of complex I (NADH:ubiquinone oxidoreductase). Complex I is one of the entry points in the respiratory chain. It oxidizes NADH and in this process translocates protons across the inner mitochondrial membrane. Eukaryotic complex I has a molecular weight almost 1 MDa and is one of the largest membrane proteins in the mitochondrial inner membrane. It consists out of more than 40 individual subunits. 14 of the subunits are conserved throughout all species and are also found in bacterial complex I. We have shown, that not only are the central subunits conserved for all species but also its basic shape is the same for the yeast Yarrowia lipolytica , for bovine complex I and bacterial complex I (Aquifex aeolicus).
We have determined the structures of Y. lipolytica complex I, bovine complex I and complex I from the bacterium A. aeolicus by three-dimensional electron microscopy. We have shown that not only the central subunits of the enzyme are conserved throughout species, but also its basic shape. Or current work focuses on the study of conformational changes during different functional states of complex I by 3D electron microscopy.
A second topic of our research is the development of new methods for 3D reconstruction of macromolecular assemblies and sub-cellular components. Methods include 3D reconstruction algorithms for conical tomography, the random conical reconstruction techniques combined with algorithms for 3D reconstruction from randomly oriented projections and techniques for reference based 3D reconstruction and refinements using Radon transform / polar Fourier transform based correlation methods. A fast reconstruction algorithm we developed is the two-step 3D Radon inversion algorithm. Currently we are developing 3D multivariate statistical techniques applicable to volumes with missing data, for the analysis of conformational variations in 3D data sets.
M. Radermacher, Chapter 1: Visualizing Functional Flexibility by Three-Dimensional Electron Microscopy: Reconstructing Complex I of the Mitochondrial Respiratory Chain. In: Methods in Enzymology, Mitochondrial Function, Part A: Mitochondrial Electron Transport Complexes and Reactive Oxygen Species, Edited by: William S. Allison and Immo E. Scheffler, (2009) Vol. 456, 3-27
T. Clason, T. Ruiz, H. Schagger, G. Peng, V. Zickermann, U. Brandt, H. Michel, M. Radermacher: The structure of eukaryotic and prokaryotic complex I. J Struct Biol (2010) 169(1):81-88
L. Yu, R.R. Snapp, T. Ruiz, M. Radermacher, Probabilistic principal component analysis with expectation maximization (PPCA-EM) facilitates volume classification and estimates the missing data. J Struct Biol. 2010, 171(1):18-30
S. Dröse, S. Krack, L. Sokolova, K. Zwicker, H.D. Barth, N. Morgner, H. Heide, M. Steger, E. Nübel, V. Zickermann, S. Kerscher, B. Brutschy, M. Radermacher, U. Brandt. Functional dissection of the proton pumping modules of mitochondrial complex I. PLoS Biol. 2011, 9(8):e1001128.
M.Radermacher, V.Rao, R.Grassucci, J.Frank, A.P.Timerman, S.Fleischer, T.Wagenknecht, Cryo-Electron Microscopy and Three-dimensional Reconstruction of the Calcium Release Channel/Ryanodine Receptor from Skeletal Muscle. J. Cell Biol. 127,1994,411-423
* indicates equal contribution
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