The selectivity filter (SF) gate in K+ channels is regulated by the occupation with K+ ions (orange circles) and a hydrogen bond network anchoring it to the pore helix (symbolized by the orange springs).
Ion channels are involved in many physiological processes. Understanding the biophysical mechanisms of transport and gating in these proteins is therefore a prerequisite for the development of targeted therapies for many different diseases. The quantitative correlation of data from different sources, e.g. electrophysiological experiments, structural biology and computer simulations is needed for a full understanding of the molecular processes involved.
We employ electrophysiological, analytical and coarse-grained simulation techniques to improve this kind of quantitative correlation and to provide new information on channel function. The combination of these methods enables an interplay between computational and functional approaches leading to a stepwise improvement of the models on either side. To maximize the clearness of the experimental data, most experiments are done one the model system of viral potassium (K+) channels. More information about this can be found in Methods.
The selectivity filter gate
The selectivity filter (SF) is the central, most conserved core of K+ channels through all realms of life and has been shown to be a gate of physiological relevance. It is modulated by the occupation with K+ ions as they permeate the channel and by an intricate hydrogen bond network anchoring the selectivity filter to the pore helix. We could determine the occupation of K+ binding sites in the SF in a functioning channel under near-physiological conditions, and showed the correctness of these results by means of the electrostatic repulsion of TPrA by the ions in the SF. The quest to understand the signal chain between ion binding and the gate is continued within the framework of the DFG Research Unit 2518 ‘DynIon’.
Modularity of ion channel pores
Ion channels are modular proteins. Their central pore can function alone. However, in most channels, additional transmembrane or soluble domains provide regulatory functions. Prominent examples are the voltage-sensing domain (VSD) and various ligand-binding domains.
However, also the pore module itself is modular. The pores of all K+, Na+ and even some Ca2+ channels share a remarkably similar structure, but evolution has resulted in different strategies, for e.g. cytosolic gates. In this project, we will transfer “functional modules”, e.g. an isolated gate or the selectivity filter, from Kcv channels to eukaryotic channels and vice versa and investigate if and how these modules can transfer their function to the host channel. Being able to understand and create channel pores as modular systems from distinct building blocks will be a huge step in terms of both understanding disease-relevant mutations in a certain domain in the context of the whole protein and also towards rational protein engineering.