Exploring and Exploiting Relevant STIM1 Domains

Calcium is an essential element for the human and animal organism, without which "life" in the sense of biochemical and cellular reactions would not be possible. Interestingly, in the course of evolution, calcium, as a doubly positively charged ion, has established itself as an enormously important cellular messenger element. It plays a dominant regulatory role in fertilization, cell differentiation, cell growth and cell division, as well as in cell type-specific reactions in response to extracellular signals such as hormones, growth factors, but also antigens in the context of an immune response. How does calcium enter the corresponding cell for all these functions? There are special channel proteins built into the cell membrane that are strictly regulated and highly selective for calcium. The regulation of these calcium influx systems is based, among other things, on voltage control and ligand activation. The system dealt with in this project is referred to as SOCE. It is the ligand-activated "Store Operated Calcium Entry" system, which is realized by 2 proteins - Orai and STIM. Since calcium plays such an impressive and important role in cellular communication, it is not surprising that a disturbed SOCE leads to diseases that are accompanied by mild symptoms on the one hand, but can also be fatal, depending on which protein domains are affected. Disorders of the SOCE system are caused by mutants of STIM and / or Orai. In this project, the focus is on investigating the functional role of STIM1. This protein acts as an intracellular calcium sensor and can switch between a resting state and an activated state in a regulatory manner. Activated STIM1 results in an interaction and activation of Orai, which leads to cellular calcium influx and the subsequent cellular response. Many point mutants of STIM1 are already known, resulting in both a permanently activated STIM1 protein (gain of function) or a permanently inactive STIM1 protein (loss of function). These are the cause of various diseases. The aim of the project is to understand the disturbed regulatory mechanisms of STIM1 mutants and to provide a basis for possible molecular therapeutic approaches. A further research topic in this project is the generation and evaluation of small STIM-binding peptides, which could also be used as a therapeutic approach for existing STIM mutants. The project is being carried out at the Johannes Kepler University Linz at the Institute of Biophysics under the guidance of Dr. Marc Fahrner. Methods of molecular biology, biochemistry, biophysics, cell culture and molecular-structural simulations are used to address the research questions.