Design and analysis of an artificial transmembrane signalling system

Dr. Max Ulbrich (Internal Medicine IV, University Medical Center Freiburg)

Signalling across the plasma membrane is often accomplished by binding of an extracellular ligand to a transmembrane receptor, which subsequently changes conformation, followed by activation of intracellular pathways via recruitment of adaptor proteins. For many receptors, the mechanical processes during this initial signalling phase remain obscure for two reasons: first, the high complexity of the proteins involved and the unknown contribution of the membrane environment make it impossible to establish a detailed structural model; and second, downstream pathways and cellular responses often exert positive or negative feedback on the signalling process, thereby hampering the analysis of the isolated receptor's behavior.
We propose to build a simplified model protein that contains the essential components of transmembrane receptors, namely an extracellular signal recognition domain, a transmembrane domain that relays information to the cell's inside, and an intracellular downstream signalling domain. In contrast to natural systems, these three modules will follow a simple design, and the lack of complex interactions with downstream components will facilitate a biophysical description based on direct observation of receptor interactions via single molecule imaging in living cells. Due to its modularity, individual components of the system can be exchanged for more complex versions, as they exist in nature, with the goal to measure the function of the naturally occurring module under well-defined conditions.