Karim Fahmy

Structural basis of biological switches and biomolecular recognition

Previous and current research

Structural changes in biopolymers  are the basis of the regulation of their biological function. Exposure of specific sites for molecular recognition as well as switching processes between states of different  activity of a biomolecule can  thus be accomplished. Understanding the underlying mechanisms allows identifying putative sites for pharmacological intervention and opens the prospect of engineering artificial molecular switches derived from the highly efficient systems that have evolved for cellular signal transduction. We are interested in the mechanisms and dynamics of such structural transitions. Using vibrational spectroscopy, we monitor in real time functionally relevant changes in the structure of proteins. Our lab has thus made major contributions to the mechanistic characterization of G-protein-coupled receptors (GPCRs). These heptahelical membrane proteins transmit extracellular signals through the plasma membrane leading to activation of GTP-binding proteins (G-proteins). We have studied the bovine visual photoreceptor rhodopsin as a prototypical model system of class I GPCRs using UV-Vis and Fourier-transform infrared (FTIR) difference spectroscopy. Recently, we have established the cross-correlation of infrared absorption and  fluorescence emission changes to observe long range coupling of conformational changes and domain movements in rhodopsin.

Future prospects and goals

Future research focuses on lipid-protein and protein-protein interactions that are of more general importance for the function of membrane and cytoskeletal proteins, respectively. The physicochemical characterization of corresponding protein domains is studied by IR and fluorescence cross-correlation spectroscopy to identify protein domains that can act as functional switches in these systems. In combination with calorimetric studies we aim at the integration of structural and thermodynamic data. Thereby, reaction models can be deduced that describe both structural and energetic aspects of conformational changes in biopolymers. Such models will serve to design artificial switches. We will extend these studies to the time-resolved investigation DNA conformation and DNA recognition. Here, we are particularly interested in the structural changes of the DNA backbone which provides an important determinant for the interaction with a large variety of specific proteins and drugs that bind to DNA.

About

1991: PhD, University Freiburg, Hans-Griesebach-Award 1991-1994: Postdoctoral Howard Hughes Medical Institute Fellow at Rockefeller University, New York 1994-2002: Habilitation, University Freiburg since 2002: Head of the Biophysics Division at the Forschungszentrum Dresden- Rossendorf (FZD)

Selected publications

Lehmann, N., Alexiev, U. & K. Fahmy (2007): Linkage between the intramembrane H-bond network around aspartic acid  83 and the cytosolic environment of helix 8 in photoactivated rhodopsin. J. Mol. Biol. 366:1129-1141.

Madathil, S., Furlinski, G. & K. Fahmy (2006): Structure and pH-Sensitivity of the Transmembrane Segment 3 of Rhodopsin. Biopolymers 82:329-333.

Fahmy, K., Merroun, M., Pollmann, K., Raff, J., Savchuk, O., Hennig, C., Selenska-Pobell, S.  (2006): Secondary structure and Pd(II) coordination in S-layer proteins from Bacillus sphaericus studied by infrared and X-ray absorption spectroscopy. Biophys. J. 91:996-1007.

Breitinger, U., Breitinger, H-G., Bauer, F., Fahmy, K., Glockenhammer, D. & C.-M. Becker (2004): Conserved high-affinity ligand binding and membrane association in the native and refolded extracellular domain of the human glycine receptor α1 subunit., J. Biol. Chem. 279: 1627-1636.

Lehmann, N., Krishna Aradhyam, G.  K. & K. Fahmy (2002): Suramin affects coupling of rhodopsin to transducin. Biophys. J. 82: 793-802.

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