Aim of Research

Why membrane proteins?

Membrane proteins represent almost a quarter of all proteins within living cells. They direct and regulate a wide range of essential functions, being responsible for such diverse process as inter- and intracellular communication, transport of nutrients and generation of energy. Their vital nature is reflected by the fact that up to 70% of current drug targets are membrane proteins. For G-Protein Coupled Receptors (GPCRs) alone, this represents a multi-billion dollar market.

 Drug target classes (Drews, Science, 287 (2000), 1960-1964)Despite their obvious pharmaceutical importance, our understanding of membrane protein function at an atomic level remains rudimentary. Detailed information about the spatial structure - a prerequisite for modern rational drug design - is rare for membrane proteins. While structure determination of membrane proteins is in principle possible, the production and purification of sufficient quantities of protein for crystallization and/or NMR structural analysis remains a major hurdle, especially for membrane proteins from higher organisms (eukaryotes, including humans).

A second major hurdle lies in bringing membrane proteins into a suitable form for structure determination by crystallography or NMR. Attempts to crystallize membrane proteins which have been solubilized with detergent have a much lower rate of success than crystallization of inherently soluble proteins, because the detergents often prevent protein-protein contacts necessary for crystallization.
As a result of these major hurdles for structural studies of membrane proteins, only around 100 membrane protein structures are currently known, compared to over 40.000 soluble proteins known near atomic level. The low chances of success in solving membrane proteins structures currently make a target-based approach, which is desirable for drug development, very difficult.

Comparison of the first decades of structure determination of soluble proteins and of membrane proteins. Inset: Protein structures deposited in the Protein Data Bank

Our goals

HALOmem aims to alleviate this problem through systematic approaches for improving the bottlenecks of membrane proteins structure determination, in particular the production and the reconstitution of membrane proteins into suitable environments for structure determination techniques. To this end, the two junior groups focus on the biochemistry of membrane proteins and on the biophysical chemistry of membranes, respectively.

Mikio Tanabe The lab of Mikio Tanabe explores a range of strategies for the recombinant expression, crystallization and structure determination of both α-helical and β-barrel membrane proteins with a particular interest in receptors involved in signaling.

Kirsten Bacia The lab of Kirsten Bacia examines interactions between proteins and lipid bilayers using in vitro reconstitution approaches and a variety of membrane mimetic systems. The reconstituted membrane systems are characterized by physicochemical and biophysical techniques, including Fluorescence Correlation Spectroscopy (FCS) and microscopy.

The two junior research groups are establishing collaborations in- and outside the university in the field of structural biology, namely (cryo-) electron microscopy, x-ray crystallography (Milton Stubbs) and NMR spectroscopy (Jochen Balbach) as well as in related fields of biochemistry, biotechnology, chemistry and physics.