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Institute of Neuropathology

Protein Biophysics and Biochemistry group (Head: G. Fritz)

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Our aim is to understand cellular processes at a detailed molecular level allowing targeted intervention and modulation of these processes. We study signaling proteins involved in neurodegenerative and tumorigenic disorders, with current focus on the the 3D structure determination of the cell surface receptor RAGE and its ligands from the S100 protein family. Moreover, we explore the challenging structures of respiratory complexes of pathogenic bacteria.

Personalia

PD. Dr. Günter FritzPrincipal Investigator+49-761-270-50780
Roya TadayonPhD Student+49-761-270-54560

Research Topics

Structure of the receptor for advanced glycation endproducts (RAGE) and its ligands

RAGE is a member of the superfamily of immunoglobulin type cell surface receptors. In endothelial cells and immune cells RAGE activation is required for the perpetuation of the immune response, whereas in neuronal cells RAGE activation leads to neurite extension and stimulates neuronal survival. RAGE has the unusual property to bind a large range of different molecules such as advanced glycation end products (AGEs), ß-sheet fibrils, and several S100 proteins. We investigate the unique structural properties of RAGE and study the functional implications of this receptor in collaboration with several research groups. Our next goal is to resolve RAGE-ligand complexes at atomic resolution.

Figure:

Modell of an active RAGE-ligand complex

S100 Proteins

The S100 protein family comprises 24 different members in human. Various diseases such as cardiomyopathies, neurodegenerative and inflammatory disorders, as well as cancer are associated with changes in expression patterns of the different S100 proteins. Several S100 proteins occur in the extracellular space where they act in a cytokine like manner through the receptor for advanced glycation end products (RAGE).

Intracellularly, S100 proteins function as Calcium (II) and Zinc (II) dependent regulators of cell division, cell growth, and motility. Some members of the S100 family bind also Copper (II) with high affinity.

We investigate the structural changes associated with metal ion binding and required for activation spectroscopic methods as well as by X-ray crystallography. Structures of S100 proteins in the inactive / active state and in complex with different signaling ions give insights into the molecular mechanisms of signal transduction.

Figure:

Structure of tumor supressor S100A2

References:


Damo SM, Kehl-Fie TE, Sugitani N, Holt ME, Rathi S, Murphy WJ, Zhang Y, Betz C, Hench L, Fritz G, Skaar EP, Chazin WJ (2013) Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens. Proc Natl Acad Sci U S A. in press

Koch M, Fritz G (2012) The structure of Ca2+-loaded S100A2 at 1.3 Å resolution. FEBS J. 279:1799-810.

Ostendorp T, Diez J, Heizmann CW, Fritz G. (2011) The crystal structures of human S100B in the zinc- and calcium-loaded state at three pH values reveal zinc ligand swapping. BBA Mol. Cell Res. 1813:1083-91.

Koch M, Diez J, Fritz G (2008) The crystal structure of human Ca2+-free S100A2 at 1.6 Å resolution. J. Mol. Biol. 378, 931-940

 

Complex Redox Proteins

All organisms catalyze redox reactions and transform the liberated energy into chemical energy for growth, motility and reproduction. The proteins involved in energy transduction require specific co-factors like flavin or metal ions like iron organized in multiple core centers. The NQR protein complex of Vibrio cholerae is investigated in close collaboration with Prof. Julia Steuber.

The properties of the redox co-factors are investigated by EPR spectroscopy and X-ray structure determination of soluble domains and of the entire complex are in progress.

Figure:

Structure of Na+-NQR

Reference:

Steuber, J., Vohl, G., Casutt, M.S., Vorburger, T., Diederichs, K., and Fritz, G. (2014) Structure of the V. cholerae Na+-pumping NADH:quinone oxidoreductaseNature 516: 62-67

Lunin VY, Lunina NL, Casutt MS, Knoops K, Schaffitzel C, Steuber J, Fritz G, Baumstark MW (2012) Low-resolution structure determination of Na(+)-translocating NADH:ubiquinone oxidoreductase from Vibrio cholerae by ab initio phasing and electron microscopy.Acta Cryst D 68:724-31.

Casutt MS, Huber T, Brunisholz R, Tao M, Fritz G, Steuber J (2012) Localization and function of the membrane-bound riboflavin in the Na+-translocating NADH:quinone oxidoreductase (Na+-NQR) from Vibrio cholerae. J Biol Chem. 285:27088-99.

Tao M, Fritz G, Steuber JM (2008) The Na+ -translocating NADH:quinone oxidoreductase (Na+ -NQR) from Vibrio cholerae enhances insertion of FeS in overproduced NqrF subunit. J. Inorg. Biochem. 102, 1366-72.