Activation of STIM1 variants by STIMATE

Fine-tuned Ca2+ homeostasis is vital for cellular processes like gene transcription, cell death and T- cell activation. Primary Ca2+ entry pathways into cells are Ca2+-release activated Ca2+ (CRAC) channels. The two key limiting molecular players of this pathway are the stromal interaction molecule 1 (STIM1), embedded in the endoplasmic reticulum (ER) and Orai1, the Ca2+ channel in the cell membrane. STIM-Orai mediated Ca2+ signalling is critically dependent on modulatory proteins that form and maintain the junctions crucial for their interaction and in turn for physiological Ca2+ homeostasis. In the present project, we functionally evaluate the undeciphered role of STIM1L and STIMATE in human Ca2+ homeostasis. First, we characterize the activation mechanism of STIM1L, the longer splice variant of the STIM gene. Using a combined approach of molecular biology, biochemistry, electrophysiology and fluorescence microscopy, our studies will further elucidate the influence of STIMATE on STIM1/STIM1L/Orai derived currents and determine the interaction sites between STIMATE and STIM1/STIM1L. Besides the important physiological function of these Ca2+ signalling proteins and their accessory fellow players, growing evidence suggests a key role of CRAC channels in cancer development. Therefore, we will take advantage of a large-scale cancer genomics database and evaluate the role of previously unknown, cancer-related mutations of STIMATE in human Ca2+ homeostasis. The results of this project will enlighten key mechanistic steps related to physiological and pathophysiological Ca2+ homeostasis in detail and lay a foundation for the development of medical treatments.